Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

Classified as probably not a substantial claim. May combine two claims.

Combining two classes of immune checkpoint blockade or combining immune checkpoint blockade with VEGF inhibitors can improve overall survival in hepatocellular carcinoma.

“However, results from recent clinical trials suggest that combining two different classes of ICBs (e.g., anti–PD-1 and anti-CTLA4), or combining ICB with other modalities such as vascular endothelial growth factor (VEGF) inhibitors, can improve overall survival (4, 5).”

• cites [4] sourceSupported
• cites [5] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Microbial-derived bile acids regulate natural killer T cell responses to liver cancer.

“Although influences of microbial-derived BAs in regulating natural killer T cell responses to liver cancer have been described (12), it remains unclear whether or how hepatic BA synthesis contributes to immune suppression, particularly its regulation of tumor-specific CD8+ T cell responses and its role in immune tolerance within the liver.”

• cites [12] sourceSupported

May combine two claims.

Liver cancers often have elevated bile acid levels, and animal models with intrahepatic bile acid retention through unchecked synthesis or export defects develop liver cancer spontaneously, suggesting direct bile acid involvement in liver cancer.

“Crucially, liver cancers often exhibit elevated levels of BAs, and animal models with intrahepatic retention of BAs through either unchecked BA synthesis or defects in BA export develop liver cancer spontaneously, suggesting the direct involvement of BAs in liver cancer (8-11).”

• cites [8] sourceNot checked — no full text of the source
• cites [9] sourceNot checked — no full text of the source
• cites [10] sourceNot checked — no full text of the source
• cites [11] sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Both Slco3a1 and Abcb1a were significantly down-regulated in exhausted CD8+ T cells relative to effector cells.

“Additionally, comparison of liver-resident effector Tag+ T cells generated from an acute Listeria monocytogenes infection with exhausted Tag+ T cells generated in AST-CRE-ERT2 mice (liver tumor) (27) indicated that both transporters Slco3a1 and Abcb1a were significantly down-regulated in exhausted CD8+ T cells relative to the effector cells (fig. S8B).”

• cites [27] sourceSupported

May combine two claims.

Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion.

“Because Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion (33-35),”

• cites [33] sourceSupported
• cites [34] sourceSupported
• cites [35] sourceCould not verify

  The passages labeled Abstract (page unavailable) link NR4A1 to T-cell dysfunction and exhaustion, but do not address NR4A2 or its relationship to NR4A1. Searches for Nr4a2 and Nurr1 found no passage in our copy saying that NR4A2 promotes T-cell exhaustion. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

May combine two claims.

Increased Tag+ T cell effector responses in sgBaat were accompanied by more CD4+ T cells and natural killer cells, elevated proinflammatory cytokines IL-12, TNF, IFN-γ, IL-15, and IL-7, and decreased tumor-promoting cytokines IL-6, LIF, and IL-11 in the liver microenvironment.

“The increased Tag+ T cell effector responses in sgBaat were also accompanied by an increase in both CD4+ T cells and natural killer cells and elevated proinflammatory cytokines [interleukin-12 (IL-12), tumor necrosis factor (TNF), IFN-γ, IL-15, IL-7] and decreased tumor-promoting cytokines such as IL-6, leukemia inhibitory factor, and IL-11 within the liver microenvironment (Fig. 2D and figs. S3,”

• cites [24] sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

NUR77 is required for isoalloLCA-induced FOXP3 expression in CD4+ T cells.

“Because NUR77 was shown to be required for isoalloLCA–induced FOXP3 expression in CD4+ T cells (32),”

• cites [32] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

CD4+ T cells require the MDR1 efflux transporter, encoded by Abcb1a/b in mice, to survive in bile acid-rich intestinal tissues.

“Previous reports have shown that CD4+ T cells require the MDR1 efflux transporter (encoded by Abcb1a/b in mice) to survive in BA-rich intestinal tissues (26).”

• cites [26] sourcePartly supported

  The Results section, “Mdr1 Enforces T Cell Homeostasis in the Presence of Conjugated Bile Acids” (page not provided), reports that Mdr1 supports effector T-cell survival during bile-acid exposure; Mdr1-null cells did not survive overnight culture with a conjugated bile acid. The claim broadens this finding to CD4+ T cells generally and to survival in intestinal tissues, whereas the reported survival test was in culture. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Bile acids are primarily synthesized by the liver from cholesterol, conjugated with taurine or glycine by BAAT, and released into the intestine.

“Bile acids (BAs) are an interesting candidate in this regard because they are primarily synthesized by the liver from cholesterol through a multistep process, conjugated with amino acids (taurine or glycine) by bile acid–CoA: amino acid N-acyltransferase (BAAT), and released into the intestine.”

• cites [7] sourcePartly supported

  The passage labeled Abstract (page unavailable) says primary bile acids are synthesized by hepatocytes from cholesterol, conjugated with glycine or taurine, and released into the duodenum. It does not identify BAAT as the enzyme responsible for conjugation, so that specific attribution is unsupported by our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Some conjugated bile acids are modified by gut microbes into secondary bile acids, and a portion recirculates to the liver and then to the bloodstream or back into bile.

“Some of these conjugated BAs are modified by gut microbes to form secondary BAs, with a portion of them recirculating back to the liver and eventually entering the bloodstream or being resecreted into bile (7).”

• cites [7] sourcePartly supported

  The Abstract (page unavailable) says that gut microbes produce secondary bile acids and that bile acids are reabsorbed and recycled through enterohepatic circulation. The Bacterial metabolism of BAs section (page unavailable) describes deconjugation as a first step. Our copy does not establish the claimed onward route into the bloodstream or explicitly say that these secondary bile acids are resecreted into bile. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Both oxidative and ER stress have been shown to contribute to T cell dysfunction across different tumor types.

“Even though both oxidative and ER stress have been shown to contribute to T cell dysfunction across different tumor types (44-51),”

• cites [44] sourcePartly supported

  The Discussion and Limitations of Study report that cholesterol-induced ER stress contributes to tumor-infiltrating CD8+ T-cell exhaustion. The cited paper supports the ER-stress part of the sentence, but the passages do not establish a contribution from oxidative stress across different tumor types. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [45] sourceSupported
• cites [46] sourceSupported
• cites [47] sourcePartly supported

  The Abstract reports that ovarian cancer induces ER stress in T cells and suppresses their mitochondrial activity and anti-tumor function; Extended Data Figure 9 also links ER stress to T cell dysfunction. The cited paper does not establish a contribution from oxidative stress or show these effects across different tumor types. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [48] sourcePartly supported

  The Results (‘Mitigating ROS or hypoxia alleviates T cell exhaustion’; page unavailable) report that reducing T-cell ROS protected against tumor-induced exhaustion, supporting the oxidative-stress part. Our copy does not show that ER stress contributes to T-cell dysfunction, or establish the claim across different tumor types; the tumor experiment described here used B16 melanoma. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [49] sourceNot checked — no full text of the source
• cites [50] sourcePartly supported

  The Results section (“Mitochondrial uncoupling suppresses T cell self-renewal”; page unavailable) links oxidative stress to impaired T cell proliferation and self-renewal and reports oxidative-stress signatures in exhausted T cells from patients with melanoma, basal cell carcinoma, and squamous cell carcinoma. The paper does not establish that ER stress contributes to T cell dysfunction, so it supports only the oxidative-stress part of the sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [51] sourcePartly supported

  The Results (pp. 6–7) link elevated mitochondrial ROS to impaired CD8 T-cell function in clear cell renal cell carcinoma and report improved activation after ROS-scavenger treatment. The cited paper does not establish a contribution from ER stress or demonstrate both forms of stress across different tumor types. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Different bile acids regulate CD8+ T cells differently: primary bile acids induce oxidative stress, while the secondary bile acid lithocholic acid inhibits T cell function through endoplasmic reticulum stress, which ursodeoxycholic acid counters.

“Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid.”

May combine two claims.

Deleting BAAT in hepatocytes to inhibit conjugated bile acid synthesis enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-PD-1 immunotherapy.

“Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy.”

May combine two claims. The quote only partly states this claim.

sgBaat tumors had a considerably higher proportion of CD8+ T cells, especially proliferating and stem-like clusters, where Tag+ CD8+ T cells were enriched.

“scRNA-seq and CITE-seq (cellular indexing of transcriptomes and epitopes) analysis of the immune cells isolated from ASTWT livers (no tumors) or from ASTAAV8-TBG-CRE livers (tumor-bearing) expressing sgSCR or sgBaat (fig. S3, D to H) revealed that sgBaat tumors displayed a considerably higher proportion of CD8+ T”

May combine two claims.

Canonical bile acid transporters Slc10a1, Slc10a2, Abcb11, Slc51a, and Slc51b were not detected in T cells, but noncanonical efflux transporters Slco3a1 and Abcb1a were readily detectable.

“Although the expression of canonical BA transporters (Slc10a1, Slc10a2, Abcb11, Slc51a, Slc51b) was not detected, two noncanonical BA efflux transporters—Slco3a1 and Abcb1a—were readily detectable in T cells (fig. S8A).”

May combine two claims.

None of the secondary bile acids had a discernible impact on survival of activated CD8+ T cells, a notable distinction from primary conjugated bile acids that appeared to worsen T cell survival more than effector functions.

“None of the secondary BAs had any discernible impact on the survival of activated CD8+ T cells, which is a notable distinction from the primary conjugated BAs that appeared to worsen T cell survival more than their effector functions (compare Fig. 3B with fig. S9A).”

May combine two claims.

IFN-γ and TNF-α production by Tag+ T cells increased in sgBaat tumors, but anti-PD-1 immune checkpoint blockade did not significantly increase their functions further.

“Additionally, IFN-γ and TNF-α cytokine production by Tag+ T cells was increased in sgBaat tumors, but their functions were not significantly increased further by anti–PD-1 ICB (fig. S4D).”

May combine two claims.

Overexpression of Slco3a1 isoform 1 or 2 in activated Tag+ T cells increased conjugated bile acid efflux, reduced γH2AX expression, and prevented T cell death in the presence of conjugated bile acids in vitro.

“Subsequently, overexpression of Slco3a1 (SLCO3A1 OE) isoform 1 or 2 within in vitro–activated Tag+ T cells increased efflux of conjugated BAs, reduced γH2AX expression, and prevented T cell death in the presence of conjugated BAs in vitro (fig. S8, H to J).”

May combine two claims.

Tag+ T cells lacking both Abcb1a and Abcb1b had reduced efflux potential, increased reactive oxygen species levels, and reduced persistence in vivo.

“Similar results were obtained in Tag+ T cells that lacked both Abcb1a and Abcb1b (sgAbcb1a/b), which displayed reduced efflux potential, increased ROS levels, and reduced persistence in vivo (fig. S8, E to G).”

May combine two claims.

Slco3a1 knockout in Tag+ T cells reduced efflux capacity and increased γH2AX expression compared with sgSCR.

“This resulted in reduced efflux capacity and increased γH2AX expression (a measure of DNA damage) compared with sgSCR (Fig. 3I and fig. S8D).”

May combine two claims.

scRNA-seq of tumor-infiltrating T cells from HCC patients showed that SLCO3A1 was more highly expressed in effector CD8+ T cells (CX3CR1+) and MAIT cells prevalent in adjacent normal livers but minimally expressed in intratumoral exhausted CD8+ T cells (LAYN+).

“Similarly, scRNA-seq analysis of tumor-infiltrating T cells from HCC patients (28) also indicated that SLCO3A1 was more highly expressed in effector CD8+ T cells (CX3CR1+) and mucosal-associated invariant T (MAIT) cells that were prevalent in the adjacent normal livers but only minimally expressed in intratumoral exhausted CD8+ T cells (LAYN+) (fig. S8C),”

• cites [28] sourceNot checked — no full text of the source

May combine two claims.

LCA, LCA bacterial metabolites isoLCA, isoalloLCA, and dehydroLCA, and to a lesser extent DCA, dose-dependently suppressed T cell cytokine production without affecting viability.

“Culturing in vitro–activated CD8+ T cells with secondary BAs indicated that LCA, as well as several LCA bacterial metabolites (isoLCA, isoalloLCA, and dehydroLCA) and, to a lesser extent, DCA, dose-dependently suppressed T cell cytokine production (percentage of IFN-γ+ TNF-a+ T cells) without affecting viability (Fig. 4C and fig. S9A).”

May combine two claims.

The total bile acid pool and select conjugated bile acids TCDCA, TCA, and GCDCA were significantly elevated in HCC liver samples, mainly non-viral HCC.

“Results showed that both the total BA pool as well as select conjugated BAs—taurochenodeoxycholic acid (TCDCA) and, to a lesser extent, taurocholic acid (TCA) and glycochenodeoxycholic acid (GCDCA)—were significantly elevated in HCC (mainly the non-viral HCC) liver samples (Fig. 1, A and B, and fig. S1A).”

May combine two claims.

B2m knockout together with sgBaat reversed the increased tumor burden seen with sgBaat alone, indicating that CD8+ T cell recognition of tumor antigens on tumor cells is required for sgBaat-mediated tumor control.

“More importantly, B2m KO (sgB2m) together with sgBaat reversed the phenotype observed with sgBaat alone that leads to increased tumor burden, indicating that CD8+ T cell recognition of tumor antigens on tumor cells is required for sgBaat-mediated control of tumors (Fig. 2H and fig. S4B).”

May combine two claims.

Tumor burden positively correlated with all major conjugated bile acids and negatively correlated with Tag+ T cell abundance, IFN-γ production, and proinflammatory cytokines IL-15, IL-12, and TNF-α.

“Furthermore, correlating the T cell responses, cytokine abundance, and intrahepatic BA levels with tumor burden from different KOs indicated that tumor burden was positively correlated with all major conjugated BAs and negatively correlated with Tag+ T cell abundance, IFN-γ production, and proinflammatory cytokines IL-15, IL-12 and TNF-α (fig. S3C).”

May combine two claims.

Baat knockout greatly reduced major conjugated bile acids while increasing unconjugated bile acids.

“As the last step in the pathway, Baat KO (sgBaat) greatly reduced the abundance of major conjugated BAs while increasing unconjugated BAs (Fig. 1, G and H, and fig. S2F).”

May combine two claims.

Treating sgBaat, but not sgSCR, tumors with anti-PD-1 antibodies significantly reduced tumor burden, with reduced liver weight, fewer tumor nodules, and heightened Tag+ T cell persistence.

“Indeed, treating sgBaat, but not sgSCR, tumors with anti–PD-1 antibodies led to a significant reduction in tumor burden, as evidenced by reduced liver weight, fewer tumor nodules, and heightened Tag+ T cell persistence (Fig. 2, I and J, and fig. S4C).”

May combine two claims.

RNA-seq of Nr4a1 knockout CD8+ T cells treated with LCA showed reduced expression of LCA-induced exhaustion genes Pdcd1, Id3, Tox, and Dusp1, while Nr4a1 knockout rescued effector genes inhibited by LCA, mainly Tbx21, Batf3, Gzma, Gzmb, and Gzmc.

“RNA-seq analysis on Nr4a1 KO CD8+ T cells (sgNr4a1) treated with LCA showed reduced expression of LCA-induced exhaustion genes, including Pdcd1, Id3, Tox, and Dusp1, whereas Nr4a1 KO rescued the expression of effector genes inhibited by LCA, mainly Tbx21, Batf3, Gzma, Gzmb, and Gzmc (fig. S9, F and G).”

May combine two claims.

sgCyp7a1 and sgBaat increased infiltration and functionality, mainly IFN-γ positivity, of Tag+ T cells within tumors.

“Adoptive transfer of Tag+ T cells into liver tumor–bearing mice with different KOs indicated that both sgCyp7a1 and sgBaat led to increased infiltration (Fig. 2, A and B) and functionality [mainly interferon-γ–positive (IFN-γ+)] of Tag+ T cells within tumors (Fig. 2C).”

May combine two claims.

BAAT expression was considerably higher in HCC than in non-HCC liver samples, mostly from NASH patients.

“Immunohistological analysis of these liver tissues revealed that BAAT expression was considerably higher in HCC than in non-HCC samples [mostly derived from nonalcoholic steatohepatitis (NASH) patients] (Fig. 1C and fig. S1, B and C).”

May combine two claims.

Neutralizing reactive oxygen species by overexpressing Catalase in Tag+ cells rescued T cell survival in vitro with TCDCA and promoted T cell persistence in vivo in liver tumors after adoptive transfer.

“Neutralizing ROS by overexpressing Catalase (CAT-OE) in Tag+ cells rescued T cell survival in vitro in the presence of TCDCA (fig. S7F) and promoted T cell persistence in vivo in liver tumors upon adoptive transfer (Fig. 3F).”

May combine two claims.

RNA-seq principal components analysis showed that discrete bile acid exposures accounted for major transcriptional differences, with isoalloLCA followed by LCA showing the most differentially expressed genes and TCA showing fewer than vehicle-treated controls.

“Principal components analysis revealed that discrete BA exposures accounted for major transcriptional differences, with isoalloLCA, followed by LCA, showing the most differentially expressed genes (DEGs) and TCA showing fewer DEGs compared with vehicle-treated control cells (fig. S9, B and C).”

May combine two claims.

Gene set enrichment analysis indicated that isoalloLCA induced genes involved in T cell exhaustion, mainly Nr4a1, Nr4a2, Tox, Bhlhe40, and Lag3, and unfolded protein response or ER stress response, mainly Eif2ak3, Atf6, Ern1, Ddit3, and Atf3, both down-regulated with UDCA.

“Gene set enrichment analysis of DEGs indicated that isoalloLCA induced genes involved in T cell exhaustion (mainly Nr4a1, Nr4a2, Tox, Bhlhe40, Lag3) and unfolded protein response or endoplasmic reticulum (ER) stress response (mainly Eif2ak3, Atf6, Ern1, Ddit3, Atf3), both of which were down-regulated with UDCA (Fig. 4E and fig. S9D).”

May combine two claims.

sgBaat tumors had lower amounts of these secondary bile acids, correlating with reduced tumor burden and increased T cell effector function.

“whereas sgBaat tumors displayed lower amounts of these secondary BAs (Fig. 4B), correlating with reduced tumor burden and increased T cell effector function.”

May combine two claims.

UDCA concentrations and/or the ratio of UDCA/LCA conjugates were significantly elevated in sgBaat tumors compared with sgSCR tumors, correlating with reduced tumor burden and increased T cell function.

“Measurement of UDCA levels in liver tumors indicated that the concentrations of UDCA and/or ratio of UDCA/ LCA conjugates were significantly elevated in sgBaat tumors compared with sgSCR tumors (Fig. 5, A and B), which correlates with reduced tumor burden and increased T cell function.”

May combine two claims.

A 1% UDCA diet was quite protective, nearly abolished tumor growth, and normalized liver weight to levels comparable to a healthy mouse.

“Importantly, 1% UDCA in the diet was quite protective and nearly abolished tumor growth and normalized liver weight to levels comparable to those of a healthy mouse (Fig. 5D).”

May combine two claims.

LCA diet led to loss of effector functions in CD4+ T cells (IFN-γ+ Th1 cells) and adoptively transferred CD8+ Tag+ T cells (IFN-γ+ TNF-α+).

“More importantly, LCA diet led to loss of effector functions in both CD4+ T cells (IFN-γ+ T helper 1 cells) and adoptively transferred CD8+ Tag+ T cells (IFN-γ+ TNF-α+) (Fig. 4H and fig. S10B).”

May combine two claims.

LCA diet was accompanied by a significant reduction in CD4+ T cells and, to a lesser extent, CD8+ T cells and increased intratumoral neutrophils.

“This was accompanied by a significant reduction in CD4+ T cells and, to a lesser extent, CD8+ T cells and increased intratumoral neutrophils (fig. S10, B and C).”

May combine two claims.

Intratumoral Tag+ T cells from LCA-fed mice gained NUR77, XBP1, and ATF3 expression, with XBP1 and ATF3 being downstream targets of the ER stress response.

“Additionally, intratumoral Tag+ T cells from LCA-fed mice gained NUR77, XBP1, and ATF3 expression (the latter two being downstream targets of the ER stress response) (Fig. 4I).”

May combine two claims.

Nr4a1/2 loss significantly promoted T cell persistence and modestly rescued T cell cytokine production in LCA-fed mice.

“Conversely, Nr4a1/2 loss significantly promoted T cell persistence and modestly rescued T cell cytokine production in LCA-fed mice.”

May combine two claims.

Knockout of ER stress sensors Atf6, Ern1, or Eif2ak3 in Tag+ T cells significantly rescued T cell IFN-γ production in LCA-fed mice but minimally affected their survival.

“More importantly, KO of the ER stress sensors Atf6, Ern1, or Eif2ak3 in Tag+ T cells significantly rescued T cell IFN-γ production in LCA-fed mice, yet minimally affected their survival (Fig. 4J and fig. S10, D and E).”

May combine two claims.

Modifying bile acid synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

“We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.”

May combine two claims.

BAAT is distinctively elevated in HCC tumor cells and correlates with increased abundance of intrahepatic primary conjugated bile acids.

“These findings indicated that BAAT is distinctively elevated in HCC tumor cells and correlates with increased abundance of intrahepatic primary conjugated BAs.”

May combine two claims.

Reducing BAAT levels or segregating patients by BAAT expression may provide a favorable response to immunotherapy.

“suggesting that reducing BAAT levels or segregating patients on the basis of BAAT expression may provide a favorable response to immunotherapy.”

May combine two claims.

Tumor-reactive T cells down-regulate efflux transporter genes, and this is associated with lower efflux potential and increased intracellular bile acid accumulation.

“Together, these results suggested that tumor-reactive T cells down-regulate expression of efflux transporter genes and that this associated with lower efflux potential and increased intracellular BA accumulation.”

May combine two claims.

Expression of bile acid efflux transporters Slco3a1 and Abcb1a/b is critical for survival of tumor-specific T cells within conjugated bile acid-rich liver tumor microenvironments, and Slco3a1 overexpression is a previously uncharacterized mechanism to boost survival of adoptively transferred T cells into HCC livers.

“Collectively, these results demonstrated that the expression of BA efflux transporters (Slco3a1 and Abcb1a/b) is critical for survival of tumor-specific T cells within conjugated BA-rich liver TMEs and that overexpression of Slco3a1 represents a previously uncharacterized mechanism to boost survival of adoptively transferred T cells into HCC livers.”

May combine two claims.

Conjugated bile acid synthesis by tumor cells suppresses antitumor T cell infiltration and function in the liver, and reducing conjugated bile acid levels creates a favorable environment for immune checkpoint blockade responsiveness.

“These results indicate that synthesis of conjugated BAs by tumor cells suppresses antitumor T cell infiltration and function in the liver and that reducing conjugated BA levels creates a conducive environment for ICB responsiveness.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Relative abundance of some secondary bile acids, mainly LCA and DCA, are risk factors for many diseases, including colorectal cancer and gall stones.

“Importantly, the relative abundance of some of the secondary BAs, mainly lithocholic acid (LCA) and deoxycholic acid (DCA), are risk factors for many diseases, including colorectal cancer and gall stones (29-31).”

• cites [29] sourceNot checked — no full text of the source
• cites [30] sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites [31] sourceNot checked — no full text of the source

May combine two claims.

Changes in secondary bile acids in sgBaat livers, mainly elevated UDCA over isoalloLCA, may dampen ER stress within tumor-reactive T cells, contributing to their elevated responses in vivo.

“This suggested that changes in secondary BAs in sgBaat livers (mainly elevated UDCA over isoalloLCA) may dampen ER stress within tumor reactive T cells, contributing to their elevated responses in vivo.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The ratio of UDCA/LCA or UDCA/DCA is often used as a diagnostic predictor of colorectal cancer susceptibility.

“The ratio of UDCA/LCA or UDCA/DCA is often used as a diagnostic predictor of colorectal cancer susceptibility (41).”

• cites [41] sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

UDCA has been previously considered protective against colon cancer.

“Although our data suggest that LCA is a risk factor for liver cancer, UDCA has been previously considered to be protective against colon cancer (39, 40).”

• cites [39] sourceNot checked — no full text of the source
• cites [40] sourceNot checked — no full text of the source

May combine two claims.

The study links bile acid synthesis to T cell responses during liver cancer and highlights the role of tissue-specific metabolism in regulating antitumor immunity.

“Our study links BA synthesis to T cell responses during liver cancer and highlights the role of tissue-specific metabolism in regulating antitumor immunity.”

May combine two claims.

LCA could promote tumorigenesis and T cell dysfunction in vivo by inducing ER stress response signaling within tumor-specific T cells.

“Altogether, these results indicate that LCA could promote tumorigenesis and T cell dysfunction in vivo by inducing ER stress response signaling within tumor-specific T cells.”

May combine two claims.

Reduction of BAAT activity reshaped bile acids in the tumor microenvironment, reducing liver-derived conjugated bile acids and some microbiome-derived LCA species while increasing UDCA, which exerted powerful effects on tumor-infiltrating T cells and promoted tumor clearance.

“Nevertheless, reduction of BAAT activity reshaped the BAs in the TME, reducing both liver-derived conjugated BAs and some microbiome-derived LCA species while increasing the other microbial-derived BA, UDCA, which exerted powerful effects on tumor-infiltrating T cells and promoted tumor clearance.”

May combine two claims.

Dietary increases in UDCA potently suppress liver cancer and promote tumor-specific T cell effector responses.

“Together, these findings indicate that dietary increases in UDCA potently suppress liver cancer and promote tumor-specific T cell effector responses.”