TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance
Open accessAbstract
Background: Identifying biomarkers that predict immunotherapy efficacy and discovering new targets for combination therapies are critical elements for improving the prognosis of bladder cancer (BLCA) patients.Methods: Firstly, we explored the expression patterns of TBX3 in normal and pan-cancer tissues and the correlation between TBX3 and the immune microenvironment using data from multiple public databases.Then, we combined various techniques, including bulk RNA sequencing, single-cell RNA sequencing, high-throughput cytokine arrays, functional experiments, ProcartaPlex multiplex immunoassays and TissueFAXS panoramic tissue quantification assays, to demonstrate that TBX3 shapes an immunosuppressive tumor microenvironment (TME) in BLCA.Results: We identified TBX3 as a key factor associated with the immunosuppressive microenvironment in BLCA through a systematic multi-omics analysis.We found that TBX3 is primarily expressed in malignant cells, where TBX3 high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment.We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3.Moreover, TBX3 reduced the cancer-killing efficiency of CD8 + T cells by decreasing the proportion of GZMB + CD8 + T cells, and knocking down TBX3 combined with anti-PD-1 treatment increased CD8 + T cell infiltration and reduced CAFs in vivo.We also validated the inverse relationship between TBX3 + malignant cells and CD8 + T cells and the positive relationship with CAFs in tissue microarrays.Lastly, we found that TBX3 predicted immunotherapy efficacy in our real-world immunotherapy cohort and multiple public cohorts.Conclusion: In summary, TBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment, and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.
AI snapshot
Written from the paper’s full text.
TL;DR
In bladder cancer, TBX3 is overexpressed, mainly in malignant cells, and drives an immunosuppressive microenvironment by transcriptionally activating TGFβ1, recruiting CAFs, and reducing GZMB+ CD8+ T cells. Targeting TBX3, alone or with anti-PD-1, reverses immunosuppression and improves antitumor efficacy in preclinical models, and high TBX3 predicts immunotherapy resistance in multiple cohorts.
Key findings
- TBX3 was higher in BLCA than normal tissue in the Xiangya and TCGA-BLCA cohorts; IHC showed moderate/high TBX3 in 60.55% of BLCA tissues versus 9.56% of para-carcinoma tissues (p < 0.0001). Single-cell and TMA analyses found TBX3 mainly in malignant cells (71.28% in TMA), with low co-expression in CD8+ T cells (0.02%) and α-SMA+ CAFs (1.02%).
- TBX3 correlated with an immunosuppressive TME: it was negatively associated with cancer-immunity cycle steps, effector memory CD4 T cells, activated CD8 T cells, effector memory CD8 T cells, activated dendritic cells, T cell-inflamed score, and immune checkpoint genes in TCGA-BLCA and Xiangya cohorts.
- Mechanistically, TBX3 bound to binding site 1 of the TGFβ1 promoter and increased TGFβ1 secretion; blocking TGFβ1 counteracted TBX3-mediated inhibition of CD8+ T cell killing and CAF marker induction, and TGFβ1 knockdown reduced tumor promotion and increased CD8+ and GZMB+ CD8+ T cells while decreasing CAFs.
- In vivo, TBX3 overexpression promoted tumor growth and decreased survival, reduced T cells/CD8+ T cells and GZMB expression, and increased CAFs; TBX3 knockdown combined with anti-PD-1 produced the strongest tumor inhibition, highest CD8+ and GZMB+ CD8+ T cell infiltration, and lowest CAFs. High TBX3 was associated with immunotherapy resistance and worse disease-free survival, including in IMvigor210 (desert immune phenotype, TC0, IC0) and additional cohorts.
Methods
- Multi-omics and clinical datasets: TCGA pan-cancer and TCGA-BLCA, GEO datasets GSE13507 and GSE48075, immunotherapy cohorts IMvigor210, GSE135222, GSE173839, and PMID26359337; Xiangya bulk RNA-seq of 57 BLCA and 13 paired normal samples (GSE188715); IHC on 109 BLCA and 73 adjacent tissues; a 50-sample BLCA TMA; and single-cell RNA-seq from five BLCA samples plus mouse tumors.
- Experimental approaches: TBX3 overexpression/knockdown in T24, TCCSUP, and MB49 cells; qRT-PCR, western blotting, ELISA, cytokine arrays, ChIP, dual-luciferase reporter assays, co-culture with CD8+ T cells and fibroblasts, flow cytometry, and TissueFAXS spatial quantification; mouse subcutaneous BLCA models treated with anti-PD-1, TGFβ1 knockdown, or nintedanib.
- Analysis: ssGSEA for 28 immune cell types, TIP cancer-immunity cycle scoring, GO/KEGG/GSEA, ROC analysis, and survival analysis; group comparisons used Student’s t test or Mann-Whitney U test, correlations used Pearson or Spearman coefficients, and p < 0.05 was significant.
Limitations
- The paper states that validation cohorts included RNA-seq and microarray data, which may introduce batch effects and biases; further research is needed to understand why tumor cells highly express TBX3; and future work will focus on designing TBX3 small-molecule nanodrug carrier inhibitors.
- Evident from the text: the immunotherapy predictive value is based on retrospective real-world and public cohorts rather than prospective clinical validation, and mechanistic causality is largely supported by cell lines and mouse models, with human TMA data showing spatial associations.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
31 of 44 cited sources checked · 14 supported · 1 flagged · accuracy not yet measured
- Findingown data
The CAF score and markers were significantly higher in the TBX3-overexpression group in scRNA-seq data.
“the CAF score and markers were significantly higher in the TBX3-overexpression group 49.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] Li Y Jiang M Aye L Luo L Zhang Y Xu F UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment Nat Commun 2024 15 1200 38331898 PMC10853547 source
The Results section (page unavailable) reports higher CAF scores and increased FAP and MMP11 expression in fibroblasts co-cultured with UPP1-overexpressing tumor cells, not TBX3-overexpressing cells. It explicitly calls the increase in the proportion of MMP11+ CAF-like fibroblasts significant, but does not use that wording for the score and marker comparisons. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Findingown data
TBX3 is primarily expressed in malignant epithelial cells and fibroblasts at the single-cell level in BLCA.
“we collected five BLCA samples for single-cell sequencing (named Xiangya scRNA) and found that TBX3 is primarily expressed in malignant epithelial cells and fibroblasts at the single-cell level (Figures 1E-F). The result was further validated using a public BLCA (PRJNA662018) scRNA-seq cohort 45.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [45] Chen Z Zhou L Liu L Hou Y Xiong M Yang Y Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma Nat Commun 2020 11 5077 33033240 PMC7545162 source
The Methods (Raw data processing and quality control) describe a bladder-cancer single-cell dataset, supporting the citation’s use to identify a validation cohort. Our copy does not identify that dataset as PRJNA662018 or report TBX3 expression in malignant epithelial cells and fibroblasts (searched: PRJNA662018, TBX3). (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Findingown data
TBX3 is negatively related to T cell inflamed score (TIS).
“In addition, TBX3 was negatively related to T cell inflamed score (TIS) 42 (Figure 2E).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [42] Ayers M Lunceford J Nebozhyn M Murphy E Loboda A Kaufman DR IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade J Clin Invest 2017 127 2930 40 28650338 PMC5531419 source
- Premisecitation
TGFβ1 promotes the infiltration of CAFs.
“Prior studies have also indicated that TGFβ1 is both a key product and a major stimulant of CAFs, promoting the accumulation of CAFs and the deposition of the ECM 47,48.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [47] Shi X Yang J Deng S Xu H Wu D Zeng Q TGF-beta signaling in the tumor metabolic microenvironment and targeted therapies J Hematol Oncol 2022 15 135 36115986 PMC9482317 source
The section on TGF-β-dependent stromal–epithelial coupling (page unavailable) says TGF-β1 induces normal fibroblasts to become CAFs and increases collagen synthesis. This supports CAF formation and a component of ECM deposition, but it does not establish that TGF-β1 promotes CAF infiltration into tumors. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [48] Chan MK Chung JY Tang PC Chan AS Ho JY Lin TP TGF-beta signaling networks in the tumor microenvironment Cancer Lett 2022 550 215925 36183857 source
- Findingown data
TBX3 overexpression significantly promoted tumor growth in mice.
“As shown in Figures 3B-D, TBX3 overexpression significantly promoted tumor growth in mice, indicating that TBX3 acts as an oncogene in BLCA.”
Quote in the paperSubstantial claim
- Findingown data
TBX3 is negatively correlated with component genes of TIS and ICI genes.
“Finally, TBX3 was negatively correlated with the component genes of TIS (Figure 2F, bottom left) and ICI genes (Figure 2F, upper right).”
Quote in the paperSubstantial claim - Findingown data
TBX3 is significantly negatively correlated with the majority of cancer-immunity cycle steps in both TCGA-BLCA and Xiangya cohorts.
“We found TBX3 was significantly negatively correlated with the majority of these steps both in the TCGA-BLCA and Xiangya cohorts (Figure 2A), indicating that TBX3 might induce an immunosuppressive microenvironment in BLCA through inhibiting the cancer-immunity cycle.”
Quote in the paperSubstantial claim - Findingown data
TBX3 is negatively correlated with immune cell infiltration in BLCA, TGCT, and THCA.
“As expected, further analysis revealed that TBX3 was negatively correlated with immune cell infiltration in BLCA, testicular germ cell tumors (TGCT), and thyroid carcinoma (THCA) (Figure S2F).”
Quote in the paperNot a substantial claim - Findingown data
Immune effector genes from CD8+ T cells, NK cells, macrophages, Th1 cells, and dendritic cells are expressed higher in the low TBX3-expressing group in TCGA-BLCA.
“Based on the median expression of TBX3 in the TCGA-BLCA cohort, we divided the TCGA-BLCA cohort into high and low TBX3-expressing groups and found that the immune effector genes from CD8+ T cells, natural killer (NK) cells, macrophages, type 1 T helper (Th1) cells, and dendritic cells were all expressed higher in the low TBX3-expressing group (Figure 2D).”
Quote in the paperSubstantial claim - Findingown data
Across 33 cancer types at the single-cell level, TBX3 is primarily expressed in malignant tumor cells, epithelial cells, and fibroblasts.
“This pan-cancer analysis indicated that TBX3 is primarily expressed in malignant tumor cells, epithelial cells, and fibroblasts across cancers (Figure 1G).”
Quote in the paperSubstantial claim - Findingown data
Most of 122 immunomodulators are significantly negatively related to TBX3 expression in several cancers, particularly BLCA.
“We assessed 122 immunomodulators, including MHC, receptors, chemokines, and immune stimulators, as reported by Charoentong et al. 40 and found that most of these immunomodulators were significantly negatively related to TBX3 expression in several cancers, particularly in BLCA (Figure S2A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Charoentong P Finotello F Angelova M Mayer C Efremova M Rieder D Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade Cell Rep 2017 18 248 62 28052254 source
- Findingown data
Co-culturing TBX3-overexpressing BLCA cells with CD8+ T cells significantly inhibited the cancer-killing efficiency of the CD8+ T cells.
“co-culturing TBX3-overexpressing BLCA cells with CD8+ T cells significantly inhibited the cancer-killing efficiency of the CD8+ T cells (Figures 5B-C).”
Quote in the paperSubstantial claim- Rests on an assumption: The co-culture experiments with BLCA cells, CD8+ T cells, and fibroblasts adequately model the human BLCA tumor microenvironment.
- Findingown data
TBX3high tumor cells increase the secretion of TGFβ1.
“We found that TBX3 is primarily expressed in malignant cells, where TBX3high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment.”
Quote in the paperSubstantial claim - Findingown data
Patients with high TBX3 expression were associated with immunotherapy resistance.
“patients with high TBX3 expression were associated with immunotherapy resistance (Figures 8A-B)”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Rests on an assumption: The association between TBX3 expression and immunotherapy resistance is causal, not due to confounding.
- Findingown data
Knockdown of TGFβ1 significantly inhibited the formation of an immunosuppressive microenvironment by increasing the percentage of CD8+ T cells, GZMB+ CD8+ T cells, and decreasing CAFs in the TME of BLCA.
“the knockdown of TGFβ1 also significantly inhibited the formation of an immunosuppressive microenvironment by increasing the percentage of CD8+ T cells (Figure S6F), GZMB+ CD8+ T cells (Figure S6G), and decreasing CAFs (Figure S6H) in the TME of BLCA.”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
- Findingown data
Knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration in vivo.
“knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo.”
Quote in the paperSubstantial claim - Findingown data
Inhibition of CAFs significantly reduced the cancer-promoting ability of TBX3.
“the inhibition of CAFs significantly reduced the cancer-promoting ability of TBX3 (Figures S7B-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
- Findingown data
TBX3 overexpression inhibited GZMB expression on CD8+ T cells.
“In addition, TBX3 overexpression inhibited GZMB expression on CD8+ T cells, suggesting that TBX3 reduces the cancer-killing efficiency of CD8+ T cells (Figure 3I).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of TGFβ1 significantly inhibited the cancer-promoting ability of TBX3 in a subcutaneous BLCA model.
“knockdown of TGFβ1 significantly inhibited the cancer-promoting ability of TBX3 (Figures S6B-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
- Findingown data
TBX3 overexpression led to increased luciferase activity in the TGFβ1 promoter region.
“Mechanistic studies revealed that TBX3 overexpression led to increased luciferase activity in the TGFβ1 promoter region”
- Also stated in: § TBX3 expression promoted the secretion of TGFβ1 · plain
“Mechanistic studies revealed that TBX3 overexpression led to increased luciferase activity in the TGFβ1 promoter region (Figure 4I).”
Quote in the paperSubstantial claim- Rests on an assumption: The luciferase reporter assays reflect endogenous TGFβ1 promoter regulation.
- Also stated in: § TBX3 expression promoted the secretion of TGFβ1 · plain
- Findingown data
TBX3 directly binds to binding site 1 of the TGFβ1 promoter.
“ChIP experiments demonstrated that TBX3 directly binds to binding site 1 of the TGFβ1 promoter (Figure 4L).”
Quote in the paperSubstantial claim - Findingown data
In tissue microarrays, there is a positive relationship between TBX3+ malignant cells and CAFs.
“We also validated the inverse relationship between TBX3+ malignant cells and CD8+ T cells and the positive relationship with CAFs in tissue microarrays.”
Quote in the paperNot a substantial claim - Findingown data
Patients with higher TBX3 expression exhibited significantly worse disease-free survival rates following treatment.
“patients with higher TBX3 expression exhibited significantly worse disease-free survival rates following treatment (Figure 8F).”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
TBX3 overexpression decreased the percentage of T cells in the tumor.
“which revealed that TBX3 overexpression decreased the percentage of T cells while increasing CAFs (Figure 3G).”
Quote in the paperSubstantial claim - Findingown data
In the IMvigor210 cohort, TBX3 expression was significantly higher in patients with low PD-L1 expression on immune cells (IC0).
“low PD-L1 expression on immune cells (IC0) (Figure 8I).”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
The formation of an immunosuppressive microenvironment was inhibited by CAF inhibition, as evidenced by lower levels of CAFs and a higher infiltration of CD8+ T cells and GZMB+ CD8+ T cells.
“The formation of an immunosuppressive microenvironment was also inhibited, as evidenced by lower levels of CAFs (Figure S7F) and a higher infiltration of CD8+ T cells (Figure S7G) and GZMB+ CD8+ T cells (Figure S7H).”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
- Findingown data
These results were statistically significant across the entire cohort.
“These results were statistically significant across the entire cohort (Figure 8E).”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
Fibroblasts co-cultured with TBX3-overexpressing BLCA cells displayed higher levels of CAF markers, including FGF2, PDGFRB, PDGFRA, FAP, and COL4A1.
“fibroblasts co-cultured with TBX3-overexpressing BLCA cells displayed higher levels of CAF markers, including FGF2, PDGFRB, PDGFRA, FAP, and COL4A1 (Figures 5D-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The co-culture experiments with BLCA cells, CD8+ T cells, and fibroblasts adequately model the human BLCA tumor microenvironment.
- Rests on an assumption: The CAF markers used are specific for cancer-associated fibroblasts.
- Findingown data
The combination of TBX3 downregulation and anti-PD-1 treatment showed the most pronounced inhibition of cancer.
“the most pronounced inhibition of cancer was observed in the group receiving a combination of TBX3 downregulation and anti-PD-1 treatment”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
- Findingown data
DEGs between high and low TBX3 expression groups in TCGA-BLCA were mainly enriched in cytokine and extracellular matrix-related pathways.
“we first performed GO and KEGG enrichment analysis based on the TCGA-BLCA cohort and found that the DEGs between the high and low TBX3 expression groups were mainly enriched on cytokine and extracellular matrix (ECM)-related pathways (Figures 4A-B).”
Quote in the paperSubstantial claim - Findingown data
Knocking down TBX3 combined with anti-PD-1 treatment reduced CAFs in vivo.
“knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo.”
Quote in the paperSubstantial claim - Findingown data
In the IMvigor210 cohort, TBX3 expression was significantly higher in patients with a desert immune phenotype.
“The IMvigor210 cohort, the largest BLCA immunotherapy cohort reported, indicated that TBX3 expression was significantly higher in patients with a desert immune phenotype (Figure 8G)”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
TBX3 overexpression promotes CAF infiltration in the TME of BLCA.
“which revealed that TBX3 overexpression decreased the percentage of T cells while increasing CAFs (Figure 3G).”
- Also stated in: § TBX3 inhibited CD8+ T cell accumulation and promoted CAFs infiltration · plain
“Flow cytometry analysis also confirmed that TBX3 overexpression promotes the infiltration of CAFs in the TME of BLCA (Figure 3K).”
- Also stated in: § TBX3 inhibited CD8+ T cell accumulation and promoted CAFs infiltration · plain
“These results were further validated by immunofluorescence staining (Figures 3J-L).”
Quote in the paperSubstantial claim - Also stated in: § TBX3 inhibited CD8+ T cell accumulation and promoted CAFs infiltration · plain
- Findingown data
Patients with low TBX3 expression were sensitive to the treatment.
“patients with low TBX3 expression were sensitive to the treatment (Figures 8C-D).”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Rests on an assumption: The association between TBX3 expression and immunotherapy resistance is causal, not due to confounding.
- Findingown data
TBX3 overexpression significantly decreased survival in mice.
“Further, TBX3 overexpression significantly decreased survival in mice (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
The enrichment of DEGs in cytokine and ECM-related pathways was validated in TCCSUP and T24 BLCA cell lines.
“Further, we validated this result in TCCSUP and T24 BLCA cell lines (Figures 4C-D).”
Quote in the paperSubstantial claim - Findingown data
The process of fibroblasts co-cultured with TBX3-overexpressing BLCA cells displaying higher CAF markers was inhibited by the TGFβ1-neutralizing antibody.
“this process was inhibited by the TGFβ1-neutralizing antibody (Figure 5D).”
Quote in the paperSubstantial claim- Rests on an assumption: The co-culture experiments with BLCA cells, CD8+ T cells, and fibroblasts adequately model the human BLCA tumor microenvironment.
- Rests on an assumption: The TGFβ1-neutralizing antibody specifically and completely blocks TGFβ1 activity without off-target effects.
- Findingown data
Blocking TGFβ1 counteracts the immunosuppressive effects of TBX3.
“We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3.”
Quote in the paperSubstantial claim - Findingown data
In tissue microarrays, there is an inverse relationship between TBX3+ malignant cells and CD8+ T cells.
“We also validated the inverse relationship between TBX3+ malignant cells and CD8+ T cells and the positive relationship with CAFs in tissue microarrays.”
Quote in the paperSubstantial claim - Findingown data
Single-cell data confirmed that overexpression of TBX3 can inhibit immune-activated pathways.
“The single cell data from Figure 3F further confirmed that overexpression of TBX3 can inhibit immune-activated pathways (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
In the IMvigor210 cohort, TBX3 expression was significantly higher in patients with low PD-L1 expression on tumor cells (TC0).
“low PD-L1 expression on tumor cells (TC0) (Figure 8H)”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
The relationship between TBX3 and BLCA molecular subtypes was further validated in the Xiangya cohort, GSE13507, and GSE48075 datasets.
“The relationship between TBX3 and BLCA molecular subtypes was further validated in the Xiangya cohort, GSE13507, and GSE48075 datasets (Figure S9).”
Quote in the paperNot a substantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
The percentage of mutated patients was higher in the low TBX3 group.
“the percentage of mutated patients was higher in the low TBX3 group (Figure S8C).”
Quote in the paperNot a substantial claim - Findingown data
TBX3 has relatively high predictive accuracy for molecular subtypes, as demonstrated by the AUC.
“The Area Under Curve (AUC) in Figure S8B demonstrated that TBX3 has relatively high predictive accuracy for molecular subtypes.”
Quote in the paperNot a substantial claim - Findingown data
Low TBX3 expression was associated with a complete response (CR) in the desert immune phenotype of the IMvigor210 cohort.
“low TBX3 expression was associated with a complete response (CR) in the desert immune phenotype of the IMvigor210 cohort (Figure 8J).”
Quote in the paperSubstantial claim- Rests on an assumption: The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
- Findingown data
Lower TBX3 expression was associated with the basal subtype of BLCA.
“lower TBX3 expression was associated with the basal subtype of BLCA”
Quote in the paperSubstantial claim- Rests on an assumption: The median expression cutoff for TBX3 in the TCGA-BLCA cohort appropriately defines high and low TBX3 groups.
- Interpretationown data
TBX3 is related to an immunosuppressive microenvironment in BLCA.
“In summary, we found that TBX3 is related to an immunosuppressive microenvironment in BLCA.”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter.
“We further demonstrated that TBX3 enhances TGFβ1 expression by binding to the TGFβ1 promoter, and blocking TGFβ1 counteracts the immunosuppressive effects of TBX3.”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 promotes TGFβ1 expression by binding to its promoter.
“In summary, TBX3 promotes TGFβ1 expression by binding to its promoter.”
Quote in the paperSubstantial claim - Premiseown data
The TBX3-binding motif in the target gene promoter includes GTGT.
“the JASPAR database showed that the TBX3-binding motif in the target gene promoter includes GTGT (Figure 4J)”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 acts as an oncogene in BLCA.
“indicating that TBX3 acts as an oncogene in BLCA.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from the MB49 mouse subcutaneous BLCA model translate to human BLCA.
- Interpretationown data
The combination of TBX3 downregulation and anti-PD-1 treatment has a synergistic effect.
“indicating a synergistic effect (Figures 6B-E).”
Quote in the paperSubstantial claim - Premiseown data
JASPAR predicted the top three binding sites for TBX3 within the TGFβ1 promoter.
“predicted the top three binding sites for TBX3 within the TGFβ1 promoter (Figure 4K)”
Quote in the paperNot a substantial claim - Interpretationreasoning
Targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.
“and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 reduces the cancer-killing efficiency of CD8+ T cells by decreasing the proportion of GZMB+ CD8+ T cells.
“Moreover, TBX3 reduced the cancer-killing efficiency of CD8+ T cells by decreasing the proportion of GZMB+ CD8+ T cells, and knocking down TBX3 combined with anti-PD-1 treatment increased CD8+ T cell infiltration and reduced CAFs in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
TBX3high tumor cells promoted the infiltration of CAFs to form an immunosuppressive microenvironment through increased TGFβ1 secretion.
“In summary, TBX3high tumor cells promoted the infiltration of CAFs to form an immunosuppressive microenvironment through increased TGFβ1 secretion.”
- Also stated in: § Discussion · plain
“We discovered that TBX3high tumor cells increase the secretion of TGFβ1, promoting CAF infiltration and creating an immunosuppressive microenvironment by inhibiting CD8+ T cell infiltration and their cancer-killing efficiency.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationown data
TBX3 reduces the cancer-killing efficiency of CD8+ T cells.
“suggesting that TBX3 reduces the cancer-killing efficiency of CD8+ T cells (Figure 3I).”
Quote in the paperSubstantial claim - Interpretationown data
TBX3 is a key factor associated with the immunosuppressive microenvironment in BLCA through systematic multi-omics analysis.
“We identified TBX3 as a key factor associated with the immunosuppressive microenvironment in BLCA through a systematic multi-omics analysis.”
Quote in the paperSubstantial claim - Interpretationown data
Patients with higher TBX3 expression appeared to be responsive only to antiangiogenic therapy.
“patients with higher TBX3 expression appeared to be responsive only to antiangiogenic therapy (Figures S8D-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The drug sensitivity predictions for chemotherapy, targeted therapy, and radiotherapy are valid.
- Interpretationown data
TBX3 promotes BLCA progression by inducing an immunosuppressive microenvironment.
“TBX3 promotes BLCA progression by inducing an immunosuppressive microenvironment”
Quote in the paperSubstantial claim - Interpretationreasoning
TBX3 is associated with resistance to immunotherapy.
“Consequently, TBX3 is associated with resistance to immunotherapy.”
Quote in the paperSubstantial claim- Rests on an assumption: The association between TBX3 expression and immunotherapy resistance is causal, not due to confounding.
- May combine two claims. 33
- Classified as probably not a substantial claim. 26
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataTBX3 expression is significantly higher in cancer tissues than in normal tissues in both the Xiangya cohort and the TCGA-BLCA cohort.
“Based on bulk RNA-seq data, we found that TBX3 was expressed significantly higher in cancer tissues as compared to normal tissues in both the Xiangya cohort 34,38 (Figure 1A) and TCGA-BLCA cohort (Figure 1B).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [34] Li H Chen J Li Z Chen M Ou Z Mo M S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8(+) T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma Adv Sci 2023 10 e2300110 PMC10477882 37414584 source
- cites [38] Hu J Yu A Othmane B Qiu D Li H Li C Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer Theranostics 2021 11 3089 108 33537076 PMC7847675 source
Classified as probably not a substantial claim.
PremisecitationNintedanib can inhibit CAF infiltration.
“It has been reported that nintedanib can inhibit CAF infiltration 50”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [50] Lee YE Go GY Koh EY Yoon HN Seo M Hong SM Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6 J Immunother Cancer 2023 11 e006130 36849201 PMC9972461 source
The Results section on MSLN-targeted CAR-NK treatment (page unavailable) reports significantly reduced CAF populations in tumor sections from nintedanib-treated mice. The Results also report fewer CAFs in treated spheroid co-cultures, but attribute that reduction to effects including CAF cell death; the paper does not establish that nintedanib inhibits CAF infiltration into tumors. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTBX3 has been shown to lead to uncontrolled cell proliferation and evasion of senescence and apoptosis, thereby promoting cancer initiation, angiogenesis, and metastasis.
“Further, TBX3 has been shown to lead to uncontrolled cell proliferation and evasion of senescence and apoptosis, thereby promoting cancer initiation, angiogenesis, and metastasis 29.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [29] Khan SF Damerell V Omar R Du Toit M Khan M Maranyane HM The roles and regulation of TBX3 in development and disease Gene 2020 726 144223 31669645 PMC7108957 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCAFs secrete growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CCL2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape.
“In addition, CAFs secrete substantial amounts of growth factors, proinflammatory cytokines, and chemokines, particularly TGF-β, IL-6, and CC-chemokine ligand 2, which recruit immunosuppressive cells into the tumor stroma and lead to immune escape 20-22.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [20] Flavell RA Sanjabi S Wrzesinski SH Licona-Limon P The polarization of immune cells in the tumour environment by TGFbeta Nat Rev Immunol 2010 10 554 67 20616810 PMC3885992 source
The section on TGFβ’s effects on innate immune cells (page unavailable) says TGFβ-mediated macrophage recruitment into skin tumours has an important role in immune escape. But the paper does not identify CAFs as the source of those signals or support the claimed secretion and recruitment roles of IL-6 and CCL2; its discussion of regulatory-cell trafficking instead mentions CCL22 produced by tumour-associated macrophages. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [21] Yang X Lin Y Shi Y Li B Liu W Yin W FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling Cancer Res 2016 76 4124 35 27216177 source
- cites [22] Gaggioli C Hooper S Hidalgo-Carcedo C Grosse R Marshall JF Harrington K Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells Nat Cell Biol 2007 9 1392 400 18037882 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 has been reported to be abnormally expressed in various carcinomas, including breast, bladder, liver, and pancreatic carcinomas.
“TBX3 has been reported to be abnormally expressed in various carcinomas, including breast, bladder, liver, and pancreatic carcinomas 25-28.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [25] Amir S Simion C Umeh-Garcia M Krig S Moss T Carraway KR Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer Brit J Cancer 2016 114 1125 34 27100732 PMC4865973 source
The Abstract Background states that Tbx3 is over-expressed in breast cancer. The References include a study of Tbx3 overexpression in pancreatic carcinoma, but the paper does not report abnormal Tbx3 expression in bladder or liver carcinoma. Thus it supports only part of the four-carcinoma list. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [26] Krstic M Macmillan CD Leong HS Clifford AG Souter LH Dales DW The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer BMC Cancer 2016 16 671 27553211 PMC4994202 source
The Abstract Results report differing TBX3 expression across breast-cancer cell lines, and the Background discusses TBX3 expression in hepatocellular carcinoma. Our copy does not report abnormal TBX3 expression in bladder or pancreatic carcinoma; searches for those cancers found no supporting passage. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [27] Wang HC Meng QC Shan ZZ Yuan Z Huang XY Overexpression of Tbx3 predicts poor prognosis of patients with resectable pancreatic carcinoma Asian Pac J Cancer Prev 2015 16 1397 401 25743805 source
- cites [28] Renard CA Labalette C Armengol C Cougot D Wei Y Cairo S Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer Cancer Res 2007 67 901 10 17283120 source
May combine two claims.
PremisecitationTGFβ1 is the primary subtype of TGF in the TME and plays a crucial role in forming a non-inflamed TME.
“Notably, TGFβ1 is the primary subtype of TGF in the TME and plays a crucial role in forming a non-inflamed TME.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [47] Shi X Yang J Deng S Xu H Wu D Zeng Q TGF-beta signaling in the tumor metabolic microenvironment and targeted therapies J Hematol Oncol 2022 15 135 36115986 PMC9482317 source
The Background (page unavailable) identifies TGF-β1 as one of three TGF-β ligands but does not say it is the primary subtype in the TME. The ‘Immune cells–epithelia metabolism coupling’ section (page unavailable) says TGF-β signaling contributes to an immunosuppressive TME, but does not specifically attribute formation of a non-inflamed TME to TGF-β1. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [48] Chan MK Chung JY Tang PC Chan AS Ho JY Lin TP TGF-beta signaling networks in the tumor microenvironment Cancer Lett 2022 550 215925 36183857 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCAFs interact with cancer cells and other cell types within the TME, playing a pivotal role in regulating tumor progression and therapeutic resistance.
“CAFs interact with cancer cells and other cell types within the TME, playing a pivotal role in regulating tumor progression and therapeutic resistance 71.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [71] Xing F Saidou J Watabe K Cancer associated fibroblasts (CAFs) in tumor microenvironment Front Biosci-Landmrk 2010 15 166 79 PMC2905156 20036813 source
The Abstract and sections 5.2–5.3 describe CAF interactions with cancer cells and immune cells that promote tumor growth, invasion, and metastasis. Section 6 reports that components of a stem-cell microenvironment can promote chemotherapy resistance in acute myeloid leukemia, but it does not establish that CAFs regulate therapeutic resistance generally. Section 7 instead attributes cancer cells’ frequent resistance to therapies largely to their genomic instability. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationCurrently, there is no reliable biomarker for predicting BLCA immunotherapy efficiency.
“Currently, there is no reliable biomarker for predicting BLCA immunotherapy efficiency.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [56] Gibney GT Weiner LM Atkins MB Predictive biomarkers for checkpoint inhibitor-based immunotherapy Lancet Oncol 2016 17 e542 51 27924752 PMC5702534 source
The Conclusion (page unavailable) says PD-L1 testing alone is insufficient to select patients for checkpoint therapy and that predictive models need further development. The PD-L1 expression section discusses bladder cancer, but the review does not specifically establish that no reliable biomarker exists for predicting immunotherapy response in BLCA. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCAFs can modify the ECM to create physical barriers that restrict T cell movement.
“CAFs can modify the ECM to create physical barriers that restrict T cell movement 74.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [74] Henke E Nandigama R Ergun S Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy Front Mol Biosci 2019 6 160 32118030 PMC7025524 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTBX3 interacts with androgen receptors, playing a key role in the progression and treatment resistance of prostate cancer.
“TBX3 interacts with androgen receptors, playing a key role in the progression and treatment resistance of prostate cancer 65.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [65] Hwang JH Arafeh R Seo JH Baca SC Ludwig M Arnoff TE CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies Elife 2022 11 e73223 35550030 PMC9135408 source
The Results section ('TBX3 and NFIC are critical for AR-positive prostate cancer cells and ART resistance'; page not provided) links TBX3 to prostate cancer cell viability and resistance to AR-targeted therapy. The Discussion (page not provided) describes TBX3 interacting with CREB5 and FOXA1, not directly with the androgen receptor. The claim’s direct-interaction and prostate-cancer-progression assertions therefore go beyond what these passages establish. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 has a complex dual transcriptional regulatory function.
“Studies have shown that TBX3 has a complex dual transcriptional regulatory function.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [59] He M Wen L Campbell CE Wu JY Rao Y Transcription repression by Xenopus ET and its human ortholog TBX3, a gene involved in ulnar-mammary syndrome P Natl Acad Sci Usa 1999 96 10212 7 PMC17868 10468588 source
The Results show that a human TBX3 domain represses transcription. The Discussion describes a different, N-terminal region of Xenopus ET that can weakly activate or repress transcription depending on context, but says its significance for human TBX3 remains unclear. Thus the paper does not establish a dual regulatory function for TBX3 itself. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe basal subtype of BLCA is known to be sensitive to immunotherapy and exhibits higher immune cell infiltration.
“which is known to be sensitive to immunotherapy and exhibits higher immune cell infiltration 43”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] Kamoun A de Reynies A Allory Y Sjodahl G Robertson AG Seiler R A Consensus Molecular Classification of Muscle-invasive Bladder Cancer Eur Urol 2020 77 420 33 31563503 PMC7690647 source
The Results (Transcriptomic characterization; page not supplied) report immune infiltration in Ba/Sq tumors. The Results (Therapeutic opportunities; page not supplied) say their immune-marker expression suggests they might be more responsive to immunotherapy, but also state that no consensus class had an expression profile clearly indicating response. Thus, the claim overstates immunotherapy sensitivity as established. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn pancreatic ductal adenocarcinoma, CAFs inhibit CD8+ T cell infiltration by secreting CXCL12.
“in pancreatic ductal adenocarcinoma, CAFs inhibit CD8+ T cell infiltration by secreting CXCL12 73.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [73] Ene-Obong A Clear AJ Watt J Wang J Fatah R Riches JC Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma Gastroenterology 2013 145 1121 32 23891972 PMC3896919 source
The Results section reports that activated pancreatic stellate cells secrete CXCL12 and that knocking it down reduces CD8+ T-cell migration toward those cells in vitro. The paper also reports fewer CD8+ T cells in the juxtatumoral compartment of PDAC, but it does not establish that CXCL12 secretion itself causes the reduced infiltration in vivo. The claim states that mechanism more definitively than the evidence supports. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 acts as a transcription activator to upregulate target gene expression.
“TBX3 acts as a transcription activator to upregulate target gene expression.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [62] Han J Yuan P Yang H Zhang J Soh BS Li P Tbx3 improves the germ-line competency of induced pluripotent stem cells Nature 2010 463 1096 100 20139965 PMC2901797 source
The paper reports that Tbx3 binds regulatory targets in embryonic stem cells and that some pluripotency-associated genes are expressed at higher levels in OSKT than OSK iPS cells (full-text section labeled Abstract; no page supplied). It does not establish that Tbx3 directly acts as a transcriptional activator of those targets; it says the precise mechanism needs clarification. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTbx3 directly activates Gata6 expression via its DNA binding activity.
“Tbx3 directly activates Gata6 expression via its DNA binding activity. TBX3 has been shown to directly bind to the promoter of the Gata6 gene, a key regulatory protein of primitive endoderm differentiation, activating the expression of this gene 78.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [78] Lu R Yang A Jin Y Dual functions of T-box 3 (Tbx3) in the control of self-renewal and extraembryonic endoderm differentiation in mouse embryonic stem cells J Biol Chem 2011 286 8425 36 21189255 PMC3048727 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCAFs can suppress anti-tumor immunity through interactions with immune effector cells, particularly CD8+ T cells.
“substantial evidence indicating that CAFs can suppress anti-tumor immunity through interactions with immune effector cells, particularly CD8+ T cells 72.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [72] Mao X Xu J Wang W Liang C Hua J Liu J Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives Mol Cancer 2021 20 131 34635121 PMC8504100 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 can enhance the proliferation of human embryonic stem cells by inhibiting p14ARF and NF-κB.
“TBX3 can enhance the proliferation of human embryonic stem cells by inhibiting p14ARF and NF-κB, which are regulators of the NF-κB signaling pathway 61.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [61] Esmailpour T Huang T TBX3 promotes human embryonic stem cell proliferation and neuroepithelial differentiation in a differentiation stage-dependent manner Stem Cells 2012 30 2152 63 22865636 PMC3517731 source
The Results and Discussion report that TBX3 over-expression increases human embryonic stem cell proliferation and represses p14ARF. They identify the other repressed molecule as NFκBIB, an inhibitor of NF-κB—not NF-κB itself—and describe the proposed mechanism as possible rather than established. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 can interact directly with HDAC5 through two crucial motifs to facilitate cell migration by downregulating E-cadherin expression in hepatocellular carcinoma.
“Tbx3 can interact directly with HDAC5 through two crucial motifs (585LFSYPYT591 and 604HRH606) to facilitate cell migration by downregulating E-cadherin expression in hepatocellular carcinoma 60.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [60] Dong L Dong Q Chen Y Li Y Zhang B Zhou F Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma Signal Transduct Tar 2018 3 22 PMC6107554 30151243 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 has also been shown to function as a tumor suppressor in fibrosarcoma and liver cancer.
“TBX3 has also been shown to function as a tumor suppressor in fibrosarcoma and liver cancer, suggesting that the role of TBX3 is cancer-specific 67,68.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [67] Willmer T Cooper A Peres J Omar R Prince S The T-Box transcription factor 3 in development and cancer Biosci Trends 2017 11 254 66 28579578 source
Section 2.3.4 states that TBX3 behaves as a tumour suppressor in transformed fibroblast and fibrosarcoma cells. The liver-cancer part is not supported: section 2.3.2 instead reports that TBX3 contributes to tumour formation in hepatoma carcinoma cells. The paper therefore supports a context-dependent role, but not the claimed tumour-suppressor role in liver cancer. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [68] Liang B Zhou Y Qian M Xu M Wang J Zhang Y TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis J Hepatol 2021 75 120 31 33577921 PMC8217095 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 can influence the development of head and neck squamous cell carcinoma by regulating the PTEN tumor-related signaling pathway.
“TBX3 can influence the development of head and neck squamous cell carcinoma by regulating the PTEN tumor-related signaling pathway 66.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [66] Burgucu D Guney K Sahinturk D Ozbudak IH Ozel D Ozbilim G Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma Bmc Cancer 2012 12 481 23082988 PMC3517435 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.
“TBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [77] Shi X Zhuang Y Chen Z Xu M Kuang J Sun XL Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset Sci Adv 2022 8 eabq2987 36383654 PMC9668310 source
- cites [78] Lu R Yang A Jin Y Dual functions of T-box 3 (Tbx3) in the control of self-renewal and extraembryonic endoderm differentiation in mouse embryonic stem cells J Biol Chem 2011 286 8425 36 21189255 PMC3048727 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationXiang Shi et al. found an enrichment of the GTGT motif in the promoters of human TAC3 and KISS1 genes and a robust stimulatory action of hTBX3 on these promoters, which promotes the expression of TAC3 and KISS1.
“Xiang Shi et al. found an enrichment of the GTGT motif in the promoters of human TAC3 and KISS1 genes and a robust stimulatory action of hTBX3 on these promoters, which promotes the expression of TAC3 and KISS1 77.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [77] Shi X Zhuang Y Chen Z Xu M Kuang J Sun XL Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset Sci Adv 2022 8 eabq2987 36383654 PMC9668310 source
May combine two claims.
Findingown dataTBX3 is significantly negatively correlated with infiltration of effector memory CD4 T cells, activated CD8 T cells, effector memory CD8 T cells, and activated dendritic cells in TCGA-BLCA, validated in the Xiangya cohort.
“TBX3 was found to be significantly negatively correlated with the infiltration of effector memory CD4 T cells, activated CD8 T cells, effector memory CD8 T cells, and activated dendritic cells (Figure 2B). All of these cells have been shown to play vital roles in anti-tumor immunity. This result was validated in the Xiangya cohort (Figure 2C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn FFPE BLCA samples, 60.55% showed moderate or high TBX3 expression, whereas only 9.56% of para-carcinoma tissues did (p < 0.0001).
“As shown in Figures 1C-D, 60.55% of BLCA tissues showed moderate or high expression of TBX3, while this rate only reached to 9.56% in para-carcinoma tissue (p < 0.0001).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAcross 33 cancer types in TCGA, TBX3 is significantly overexpressed in BLCA, COAD, ESCA, and READ, and significantly downregulated in CESC and HNSC.
“As shown in Figure S1, TBX3 was significantly overexpressed in BLCA, colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), and rectum adenocarcinoma (READ). Conversely, it was significantly downregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and head and neck squamous cell carcinoma (HNSC).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWhen TGFβ1 was blocked with a TGFβ1-neutralizing antibody, the cancer-killing efficiency of CD8+ T cells significantly increased, along with an increased proportion of IFN-γ+ and GZMB+ CD8+ T cells.
“when TGFβ1 was blocked with a TGFβ1-neutralizing antibody, the cancer-killing efficiency of CD8+ T cells significantly increased, along with an increased proportion of IFN-γ+ and GZMB+ CD8+ T cells (Figures 5B-C).”
Quote in the paperSubstantial claim- Rests on an assumption: The co-culture experiments with BLCA cells, CD8+ T cells, and fibroblasts adequately model the human BLCA tumor microenvironment.
- Rests on an assumption: The TGFβ1-neutralizing antibody specifically and completely blocks TGFβ1 activity without off-target effects.
May combine two claims.
Findingown dataTBX3 was mainly expressed in BLCA cells (71.28%), compared with co-expression ratio of TBX3+ CD8+ T cells (0.02%) and TBX3+ α-SMA+ CAFs (1.02%).
“Compared with the co-expression ratio of TBX3+ CD8+ T cells (0.02%) and TBX3+ α-SMA+ CAFs (1.02%), TBX3 was mainly expressed in BLCA cells (71.28%), which revealed similar results as the scRNA sequencing (Figures 7C-D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe T cell subtype affected by TBX3 overexpression is CD8+ T cells, not CD4+ T cells.
“Further, flow cytometry analysis showed that the affected T cell subtype was CD8+ T cells, not CD4+ T cells (Figure 3H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAs the distance from TBX3+ CK19+ cells increased, the number of CD8+ T cells gradually increased, while the CAFs decreased.
“as the distance from TBX3+ CK19+ cells increased, the number of CD8+ T cells gradually increased, while the CAFs decreased (Figure 7D-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The spatial distance analysis is meaningful for inferring cell-cell interactions.
May combine two claims.
Findingown dataTumors with low TBX3 expression exhibited inflammatory phenotypes, with a large number of CD8+ T cells infiltrating the tumor area, while tumor-associated fibroblasts infiltrated significantly less.
“Tumors with low TBX3 expression exhibited inflammatory phenotypes, with a large number of CD8+ T cells infiltrating the tumor area, while tumor-associated fibroblasts infiltrated significantly less (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataTBX3 expression is associated with immunotherapy resistance and predicts immunotherapy efficacy in a real-world immunotherapy cohort and multiple public cohorts.
“Lastly, we found that TBX3 predicted immunotherapy efficacy in our real-world immunotherapy cohort and multiple public cohorts.”
- Also stated in: § Introduction · plain
“Meanwhile, combining our own data with multiple public real-world immunotherapy cohorts, we found that TBX3 expression was associated with immunotherapy resistance.”
Quote in the paperSubstantial claim- Also stated in: § Introduction · plain
May combine two claims.
Findingown dataEither downregulating TBX3 or anti-PD-1 treatment alone significantly inhibited the growth of BLCA and improved survival probability in vivo.
“either downregulating TBX3 or anti-PD-1 treatment alone significantly inhibited the growth of BLCA and improved survival probability in vivo (Figures 6B-E).”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
May combine two claims.
Findingown dataIn TBX3-overexpressing TCCSUP cells, various cytokines showed significant changes, with TGFβ1 being the most notably altered.
“We found significant changes in various cytokines in the TBX3-overexpressing BLCA cells, with TGFβ1 being the most notably altered (Figure 4F).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe combination group showed the highest infiltration of CD8+ T cells and GZMB+ CD8+ T cells, along with the lowest levels of CAFs.
“this combination group showed the highest infiltration of CD8+ T cells (Figure 6F) and GZMB+ CD8+ T cells (Figure 6G), along with the lowest levels of CAFs (Figure 6H).”
Quote in the paperSubstantial claim- Rests on an assumption: The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
May combine two claims.
Findingown dataHigh expression of TBX3 in tumor cells (CK19+) showed non-inflammatory phenotypes, and extensive expression of TBX3 in tumor cells resulted in a large accumulation of CAFs and inhibited CD8+ T cell infiltration in the tumor area.
“high expression of TBX3 in tumor cells (CK19+) showed non-inflammatory phenotypes, and extensive expression of TBX3 in tumor cells resulted in a large accumulation of CAFs and inhibited CD8+ T cell infiltration in the tumor area (Figure 7B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUpregulating TBX3 in BLCA cells increased TGFβ1 expression, while downregulating TBX3 decreased TGFβ1 expression.
“Upregulating TBX3 in BLCA cells increased TGFβ1 expression, while downregulating TBX3 decreased TGFβ1 expression (Figures 4G-H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMutation of binding site 1 reduced the activity of the TGFβ1 promoter, indicating the importance of binding site 1 for TBX3-mediated activation of the TGFβ1 promoter.
“our study showed that mutation of binding site 1 reduced the activity of the TGFβ1 promoter, indicating the importance of binding site 1 for TBX3-mediated activation of the TGFβ1 promoter (Figure 4N).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPathways related to ECM, tumor invasiveness, collagen formation, and TGF-β1 were all significantly activated in the TBX3-overexpression group.
“pathways related to ECM, tumor invasiveness, collagen formation, and TGF-β1 were all significantly activated in the TBX3-overexpression group (Figures 5G-J).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe combination treatment reverses the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy in BLCA.
“These findings suggested that the combination treatment reverses the immunosuppressive TME, thereby enhancing the efficacy of immunotherapy in BLCA.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataTBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment.
“In summary, TBX3 promotes BLCA progression and immunotherapy resistance by inducing an immunosuppressive microenvironment, and targeting TBX3 could enhance the efficacy of immunotherapy for BLCA.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from the MB49 mouse subcutaneous BLCA model translate to human BLCA.
May combine two claims.
Interpretationown dataTBX3high tumor cells promote CAF infiltration via increased TGFβ1 secretion, thereby forming an immunosuppressive microenvironment.
“We found that TBX3 is primarily expressed in malignant cells, where TBX3high tumor cells increase the secretion of TGFβ1, which promotes the infiltration of cancer-associated fibroblasts (CAFs), thereby forming an immunosuppressive microenvironment.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe result confirmed the spatially exclusive relationship between TBX3 and effector T cells, which may be the cause of immunotherapy resistance.
“This result confirmed the spatially exclusive relationship between TBX3 and effector T cells, which may be the cause of immunotherapy resistance.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationAlthough there are some studies indicating TBX3 is an oncogene in BLCA, the role of TBX3 in the TME and tumor progression is not fully understood.
“Although there are some studies indicating TBX3 is an oncogene in BLCA 31,32, the role of TBX3 in the TME and tumor progression is not fully understood.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [31] Du HF Ou LP Yang X Song XD Fan YR Tan B A new PKCalpha/beta/TBX3/E-cadherin pathway is involved in PLCepsilon-regulated invasion and migration in human bladder cancer cells Cell Signal 2014 26 580 93 24316392 source
- cites [32] Huang L Shao W Wang X Li F Mao W TBX3 stimulates proliferation and stem cell self-renewal in bladder carcinoma Histol Histopathol 2023 38 65 72 35856500 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTBX3 is highly expressed in mammary tissues, and its overexpression is associated with the occurrence and progression of breast cancer.
“TBX3 is highly expressed in mammary tissues, and its overexpression is associated with the occurrence and progression of breast cancer.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] Yarosh W Barrientos T Esmailpour T Lin L Carpenter PM Osann K TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases Cancer Res 2008 68 693 9 18245468 source
May combine two claims.
Interpretationown dataPatients with lower TBX3 expression might be sensitive to immunotherapy, radiotherapy, chemotherapy, and Anti-HER2 (ErbB2) therapy.
“patients with lower TBX3 expression might be sensitive to immunotherapy, radiotherapy, chemotherapy, and Anti-HER2 (ErbB2) therapy.”
Quote in the paperSubstantial claim- Rests on an assumption: The drug sensitivity predictions for chemotherapy, targeted therapy, and radiotherapy are valid.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTBX3 can promote the proliferation, migration, and invasion of breast cancer cells through various mechanisms while inhibiting apoptosis.
“TBX3 can promote the proliferation, migration, and invasion of breast cancer cells through various mechanisms while inhibiting apoptosis 64.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] Yarosh W Barrientos T Esmailpour T Lin L Carpenter PM Osann K TBX3 is overexpressed in breast cancer and represses p14 ARF by interacting with histone deacetylases Cancer Res 2008 68 693 9 18245468 source
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Premisenone givenThe mechanisms by which tumor cells mediate CAFs are less understood.
“However, the mechanisms by which tumor cells mediate CAFs are less understood.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCAFs reduce CD8+ T cell recruitment by releasing IL-6 and TGF-β, inhibiting their cytotoxic activity against tumor cells.
“They also reduce CD8+ T cell recruitment by releasing IL-6 and TGF-β, inhibiting their cytotoxic activity against tumor cells 75,76.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [75] Kato T Noma K Ohara T Kashima H Katsura Y Sato H Cancer-Associated Fibroblasts Affect Intratumoral CD8(+) and FoxP3(+) T Cells Via IL6 in the Tumor Microenvironment Clin Cancer Res 2018 24 4820 33 29921731 source
- cites [76] Thomas DA Massague J TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance Cancer Cell 2005 8 369 80 16286245 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOur validation cohorts included RNA-seq and microarray data, which may have introduced batch effects and biases.
“our validation cohorts included RNA-seq and microarray data, which may have introduced batch effects and biases.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTBX3 is a member of the T-box transcription factor family, playing a crucial regulatory role in embryonic development and organ formation.
“TBX3 is a member of the T-box transcription factor family, playing a crucial regulatory role in embryonic development and organ formation 23.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Dong L Lyu X Faleti OD He ML The special stemness functions of Tbx3 in stem cells and cancer development Semin Cancer Biol 2019 57 105 10 30268432 source
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningTargeting TBX3 could enhance the efficacy of immunotherapy for BLCA in the future.
“targeting TBX3 could enhance the efficacy of immunotherapy for BLCA in the future.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The role of TBX3 in regulating the TME immune status is less studied.
“However, the role of TBX3 in regulating the TME immune status is less studied.”
The paper relies on this without support.
Findings from the MB49 mouse subcutaneous BLCA model translate to human BLCA.
“A subcutaneous BLCA model was created by injecting MB49 cells with TBX3 overexpression or a negative control (Figure 3A).”
The paper relies on this without support.
The co-culture experiments with BLCA cells, CD8+ T cells, and fibroblasts adequately model the human BLCA tumor microenvironment.
“We co-cultured TBX3-overexpressing BLCA cells with CD8+ T cells and fibroblasts in order to validate the key role of TGFβ1 in shaping an immunosuppressive TME (Figure 5A).”
The paper relies on this without support.
The mouse subcutaneous BLCA model reflects human BLCA progression and immunotherapy response.
“We then knocked down TGFβ1 in the TBX3-overexpressing MB49 cell line and constructed a subcutaneous BLCA model (Figure S6A).”
The paper relies on this without support.
The TGFβ1-neutralizing antibody specifically and completely blocks TGFβ1 activity without off-target effects.
“when TGFβ1 was blocked with a TGFβ1-neutralizing antibody”
The paper relies on this without support.
The public databases and real-world cohorts used are reliable and comparable for assessing TBX3 expression and immunotherapy response.
“The IMvigor210 cohort, the largest BLCA immunotherapy cohort reported, indicated that TBX3 expression was significantly higher in patients with a desert immune phenotype (Figure 8G)”
The paper relies on this without support.
The median expression cutoff for TBX3 in the TCGA-BLCA cohort appropriately defines high and low TBX3 groups.
“We categorized the TCGA-BLCA cohort into two groups based on the median expression of TBX3”
The paper relies on this without support.
The drug sensitivity predictions for chemotherapy, targeted therapy, and radiotherapy are valid.
“The findings indicated that patients with lower TBX3 expression might be sensitive to immunotherapy, radiotherapy, chemotherapy, and Anti-HER2 (ErbB2) therapy.”
The paper relies on this without support.
The spatial distance analysis is meaningful for inferring cell-cell interactions.
“we performed counts of CD8+ T cells and CAFs within the TBX3 expression gradients in tumor cells (CK19+) (0-25 µm, 25-50 µm, 50-100 µm, and 100-150 µm).”
The paper relies on this without support.
The CAF markers used are specific for cancer-associated fibroblasts.
“fibroblasts co-cultured with TBX3-overexpressing BLCA cells displayed higher levels of CAF markers, including FGF2, PDGFRB, PDGFRA, FAP, and COL4A1”
The paper relies on this without support.
The luciferase reporter assays reflect endogenous TGFβ1 promoter regulation.
“Mechanistic studies revealed that TBX3 overexpression led to increased luciferase activity in the TGFβ1 promoter region”
The paper relies on this without support.
The association between TBX3 expression and immunotherapy resistance is causal, not due to confounding.
“patients with high TBX3 expression were associated with immunotherapy resistance”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting anti-PD-1 dosing intervals
MajorThe Methods state that anti-PD-1 or control was administered every two days for five treatments, while the Results describe the same treatment as occurring every three days for five cycles.
“Treatments were administered every two days for a total of five times.”
“the cells were treated with anti-PD-1 or IgG2a isotype antibody every three days for five cycles (Figure 6A).”
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Zhu, X., Li, Y., Liu, H., et al. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1595523 · Cited by 19 · see citing works
“These factors not only reshape the ECM structure but also recruit immunosuppressive cells (17).”
Self-citationThe ZNF737-CXCL10 axis drives immune exclusion and resistance to anti-PD-1 therapy in bladder cancer
Gao, X., Liu, J., Deng, D., Xiao, J., Liu, Y., Yan, L., Yang, W., Dai, Z., Wen, X., Zu, X., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116443 · Cited by 3 · see citing works
Self-citationGATA6 and TBX3 gene expressions analysis of indirect inguinal hernia sacs in children
Kizilkaya, O., Köprülü, M. S., Gürkan, H., & İnan, M. (2025) · Pediatric Surgery International · doi:10.1007/s00383-025-06065-z · Cited by 1 · see citing works
Dong, Y., & Su, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1821743 · Cited by 1 · see citing works
“Spatial communication analysis revealed markedly increased CAF-malignant cell and CAF-immune cell interactions in recurrent tumors, a fi nding fi rst observed at the spatial level (171).”
InfluentialXin, S., Su, J., Zhao, L., et al. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06109-0
“In bladder cancer, elevated TGFβ1 levels facilitate the infiltration of cancer-associated fibroblasts (CAFs), thereby fos - tering an immunosuppressive microenvironment [31].”
Yang, L., Zhou, D., Cao, K., Mao, D., Wang, C., Wei, T., Deng, Y. Q., Yi, Z., Li, W., & Chen, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1800910
“Concurrently, Tregs recruited via kynurenine metabolites secrete high levels of TGF-b and IL-10, which not only dampen NK cell cytotoxicity but also drive further epithelial-mesenchymal transition (EMT) in the tumor, closing the loop of resistance (73 – 75).”
Self-citationZHU, J., Zhang, C., Yu, D., Zhou, L., Zhong, Q., Jiang, J., Jin, Z., Qiu, X., Chen, J., Zhu, J., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9879994/v1
Self-citationOtx2 directly regulates tbx3 expression during early eye formation.
Ribeiro-Silva, J., Wong, K. A., & Viczian, A. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.111285
- Authors
- Liu, Z., Zhang, C., Xiao, J., He, Y., Liang, H., Huang, J., Cai, Z., Yi, Z., Chen, M., Li, Y., Zhang, J., liu, F., Ren, P., Li, H., Chen, J., Fan, B., Hu, J., Zu, X., & Deng, D.
- Affiliations
- Central South University (CN)
- Tongji Hospital (CN)
- Second People Hospital of Hunan (CN)
- Guiyang Medical University (CN)
- Corresponding author
- Deng, Dingshan
- ORCID
- Venue
- Theranostics
- Publisher
- Ivyspring International Publisher
- Published
- 2025-01-06
- Volume
- 15
- Issue
- 5
- Pages
- 1966-1986
- ISSN
- 1838-7640 (ISSN-L)
- PMC
- PMC11780534
- OpenAlex
- W4406124690
- Cited by
- 8
- References
- 74
- Citations by year
- 2026: 6 · 2025: 2
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Theranostics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (82303760, 82070785, 82373337)
- Guizhou Medical University
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TBX3, bladder cancer, immunosuppressive tumor microenvironment, immunotherapy resistance, TGF-β1, cancer-associated fibroblasts, CD8+ T cells, granzyme B, anti-PD-1 therapy, combination therapy targets
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Urinary Bladder Neoplasms, Humans, Immunotherapy, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, T-Box Domain Proteins, Cell Line, Tumor, Mice, Transforming Growth Factor beta1, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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