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Cited by 163Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesTGF-β signaling in diseases

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Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers

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Yi, Ming, Niu, Mengke, Zhang, Jing, Li, Shiyu, Zhu, Shuangli, Yan, Yongxiang, Li, Ning, Zhou, Pengfei, Chu, Qian, Wu, Kongming·2021·Journal of Hematology & Oncology
DOI 10.1186/s13045-021-01155-6PMC PMC8442312
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Abstract

Background: Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn 2+) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods: The effect of Mn 2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn 2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn 2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results: Mn 2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn 2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn 2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn 2+ plus anti-PD-L1 therapy, Mn 2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn 2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn 2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion: Combining Mn 2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.

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Fig. 1 Mn2+ activated STING pathway and promoted dendritic cell (DC) maturation. a–c Western blotting assays and ELISAs exploring the effect of Mn2+ treatment on STING pathway in human monocyte-derived DCs (MoDCs) and murine bone marrow-derived DCs (BMDCs). After 1 mM Mn2+ or other divalent cations including Ca2+ and Mg2+ treatment for 24 h, the levels of p-STING, STING, p-TBK1, TBK1, p-IRF3, and IFN-β were measured. d–e The dose-dependent effect and toxicity of Mn2+ in vitro. Human MoDCs and murine BMDCs were treated with different concentrations of Mn2+ for 24 h. The IFN-β concentration in the supernatant was measured by ELISA, and the viability of MoDCs and BMDCs was determined by AO/PI double staining (n = 2 technical replicates). f–i Flow cytometry assays showed that Mn2+ promoted DC maturation. After 1 mM Mn2+ or 20 ng/ml LPS (positive control) treatment for 24 h, the mean fluorescence intensities (MFIs) of CD80, CD86, and HLA-DR on human MoDCs were measured. After 0.5 mM Mn2+ or 20 ng/ml LPS treatment for 24 h, the MFIs of CD80, CD86, and I-A/I-E on murine BMDCs were measured (n = 3 technical replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to the last group when not marked with lines. MoDC: monocyte-derived dendritic cell; BMDC: bone marrow-derived dendritic cell; MFI: mean fluorescence intensity
Fig. 1 Mn2+ activated STING pathway and promoted dendritic cell (DC) maturation. a–c Western blotting assays and ELISAs exploring the effect of Mn2+ treatment on STING pathway in human monocyte-derived DCs (MoDCs) and murine bone marrow-derived DCs (BMDCs). After 1 mM Mn2+ or other divalent cations including Ca2+ and Mg2+ treatment for 24 h, the levels of p-STING, STING, p-TBK1, TBK1, p-IRF3, and IFN-β were measured. d–e The dose-dependent effect and toxicity of Mn2+ in vitro. Human MoDCs and murine BMDCs were treated with different concentrations of Mn2+ for 24 h. The IFN-β concentration in the supernatant was measured by ELISA, and the viability of MoDCs and BMDCs was determined by AO/PI double staining (n = 2 technical replicates). f–i Flow cytometry assays showed that Mn2+ promoted DC maturation. After 1 mM Mn2+ or 20 ng/ml LPS (positive control) treatment for 24 h, the mean fluorescence intensities (MFIs) of CD80, CD86, and HLA-DR on human MoDCs were measured. After 0.5 mM Mn2+ or 20 ng/ml LPS treatment for 24 h, the MFIs of CD80, CD86, and I-A/I-E on murine BMDCs were measured (n = 3 technical replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to the last group when not marked with lines. MoDC: monocyte-derived dendritic cell; BMDC: bone marrow-derived dendritic cell; MFI: mean fluorescence intensityCC BY · PubMed Central
Fig. 2 Mn2+ treatment upregulated PD-L1 and synergized YM101 in one-way mixed lymphocyte reaction (MLR) assay. a–b The effect of Mn2+ treatment on PD-L1 expression on dendritic cells (DCs). After 1 mM Mn2+ treatment for 24 h, the mean fluorescence intensity (MFI) of PD-L1 on MoDCs was measured. After 0.5 mM Mn2+ treatment for 24 h, MFI of PD-L1 on BMDCs was measured (n = 3 technical replicates). c–k MLR assay exploring the synergistic effect between Mn2+ treatment and YM101. BMDCs from BALB/c mice were used as stimulator cells, and splenocytes from C57BL/6 mice were used as responder cells. The immature BMDCs were treated with 0.5 mM Mn2+ or saline for 24 h. The ratio of responder to stimulator was 2:1. Then, TGF-β1 (20 ng/ml) and antibodies (105 pM) were added to the mixed cells. After culture for 96 h, the ratio of daughter CD8+ T cell and the cytokine levels in the supernatant were measured (n = 4 technical replicates). The ratio of daughter CD8+ T cell by CFSE dilution assays (c) and the cytokine levels were measured by LEGENDplex™ MU Th Cytokine Panel. The cytokine levels were visualized by heatmap (d). The levels of IFN-γ, TNF-α, IL-4, IL-5, IL-6, IL-10, and IL-13 are shown (e–k). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to the last group when not marked with lines. MoDC: monocyte-derived dendritic cell; BMDC: bone marrow-derived dendritic cell; MFI: mean fluorescence intensity; MLR: mixed lymphocyte reaction
Fig. 2 Mn2+ treatment upregulated PD-L1 and synergized YM101 in one-way mixed lymphocyte reaction (MLR) assay. a–b The effect of Mn2+ treatment on PD-L1 expression on dendritic cells (DCs). After 1 mM Mn2+ treatment for 24 h, the mean fluorescence intensity (MFI) of PD-L1 on MoDCs was measured. After 0.5 mM Mn2+ treatment for 24 h, MFI of PD-L1 on BMDCs was measured (n = 3 technical replicates). c–k MLR assay exploring the synergistic effect between Mn2+ treatment and YM101. BMDCs from BALB/c mice were used as stimulator cells, and splenocytes from C57BL/6 mice were used as responder cells. The immature BMDCs were treated with 0.5 mM Mn2+ or saline for 24 h. The ratio of responder to stimulator was 2:1. Then, TGF-β1 (20 ng/ml) and antibodies (105 pM) were added to the mixed cells. After culture for 96 h, the ratio of daughter CD8+ T cell and the cytokine levels in the supernatant were measured (n = 4 technical replicates). The ratio of daughter CD8+ T cell by CFSE dilution assays (c) and the cytokine levels were measured by LEGENDplex™ MU Th Cytokine Panel. The cytokine levels were visualized by heatmap (d). The levels of IFN-γ, TNF-α, IL-4, IL-5, IL-6, IL-10, and IL-13 are shown (e–k). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to the last group when not marked with lines. MoDC: monocyte-derived dendritic cell; BMDC: bone marrow-derived dendritic cell; MFI: mean fluorescence intensity; MLR: mixed lymphocyte reactionCC BY · PubMed Central
Fig. 3 Mn2+ plus YM101 therapy had a potent and durable antitumor activity in vivo. All mice were treated every other day for 12 days. For Mn2+ administration, mice received 5 mg/kg Mn2+ intranasally or intratumorally. For Ab treatment, mice were treated with equivalent mole hIgG (6.6 mg/kg), α-PD-L1 (6.6 mg/kg), or YM101 (9 mg/kg) by intraperitoneal injection. a–c BALB/c mice were subcutaneously inoculated in the right groin with 1 × 106 CT26 cells on day 0. Tumor-bearing mice were randomized into six groups: Isotype control, Mn2+, α-PD-L1, Mn2+ plus α-PD-L1, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment started on day 4. The representative images of CT26 tumors, tumor growth curves, and tumor weights are shown. d–f BALB/c mice were inoculated in the right mammary fat pad with 5 × 105 EMT-6 cells on day 0. Tumor-bearing mice were randomized into six groups: Isotype control, Mn2+, α-PD-L1, Mn2+ plus α-PD-L1, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment was initiated on day 4. The representative images of EMT-6 tumors, tumor growth curves, and tumor weights are shown. g–i BALB/c mice were subcutaneously inoculated in the right groin with 2 × 106 H22 cells on day 0. Tumor-bearing mice were randomized into four groups: Isotype control, Mn2+, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment started on day 4. The representative images of H22 tumors, tumor growth curves, and tumor weights are shown. j–l C57BL/6 mice were subcutaneously inoculated with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (eight mice for each group). The representative images of B16 tumors, tumor growth curves, and tumor weights are shown. (m) The schematic diagram of the rechallenge assay. BALB/c mice were inoculated with 3 × 105 EMT-6 cells in the right mammary fat pad. Therapy was initiated on day 1. Mice received six times of treatments in 12 days. One week after the last treatment, the cured or treatment-naïve mice were rechallenged with 3 × 105 EMT-6 cells. (n–o) The representative images of EMT-6 tumors and tumor growth curves in the rechallenge assay are shown. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to Mn2+ plus YM101 therapy when not marked with lines. CR: complete regression
Fig. 3 Mn2+ plus YM101 therapy had a potent and durable antitumor activity in vivo. All mice were treated every other day for 12 days. For Mn2+ administration, mice received 5 mg/kg Mn2+ intranasally or intratumorally. For Ab treatment, mice were treated with equivalent mole hIgG (6.6 mg/kg), α-PD-L1 (6.6 mg/kg), or YM101 (9 mg/kg) by intraperitoneal injection. a–c BALB/c mice were subcutaneously inoculated in the right groin with 1 × 106 CT26 cells on day 0. Tumor-bearing mice were randomized into six groups: Isotype control, Mn2+, α-PD-L1, Mn2+ plus α-PD-L1, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment started on day 4. The representative images of CT26 tumors, tumor growth curves, and tumor weights are shown. d–f BALB/c mice were inoculated in the right mammary fat pad with 5 × 105 EMT-6 cells on day 0. Tumor-bearing mice were randomized into six groups: Isotype control, Mn2+, α-PD-L1, Mn2+ plus α-PD-L1, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment was initiated on day 4. The representative images of EMT-6 tumors, tumor growth curves, and tumor weights are shown. g–i BALB/c mice were subcutaneously inoculated in the right groin with 2 × 106 H22 cells on day 0. Tumor-bearing mice were randomized into four groups: Isotype control, Mn2+, YM101, and Mn2+ plus YM101 (eight mice for each group). Treatment started on day 4. The representative images of H22 tumors, tumor growth curves, and tumor weights are shown. j–l C57BL/6 mice were subcutaneously inoculated with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (eight mice for each group). The representative images of B16 tumors, tumor growth curves, and tumor weights are shown. (m) The schematic diagram of the rechallenge assay. BALB/c mice were inoculated with 3 × 105 EMT-6 cells in the right mammary fat pad. Therapy was initiated on day 1. Mice received six times of treatments in 12 days. One week after the last treatment, the cured or treatment-naïve mice were rechallenged with 3 × 105 EMT-6 cells. (n–o) The representative images of EMT-6 tumors and tumor growth curves in the rechallenge assay are shown. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to Mn2+ plus YM101 therapy when not marked with lines. CR: complete regressionCC BY · PubMed Central
Fig. 4 Mn2+ plus YM101 therapy prolonged survival and inhibited tumor metastasis. a–b The overall survival curves of EMT-6-bearing and B16-bearing mice receiving the treatment of combination therapies or monotherapies. BALB/c mice were challenged with 3 × 105 EMT-6 cells on day 0. Therapy was initiated on day 2 (8 mice for each group). The survival status of mice was monitored for 45 days. C57BL/6 mice were subcutaneously inoculated with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (8 mice for each group). The survival status of mice was monitored for 4 weeks. c The representative images of lung tissues of mice receiving the treatment of combination therapies or monotherapies. C57BL/6 mice were intravenously injected with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (8 mice for each group). 21 days after inoculation, the mice were euthanized, and the lung tissues were collected. d The number of B16 tumor nodules in lung tissues of mice receiving the treatment of combination therapies or monotherapies. e The weights of lung tissues of mice receiving the treatment of combination therapies or monotherapies. f The representative images of H&E staining of lung tissues of mice receiving the treatment of combination therapies or monotherapies. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatment
Fig. 4 Mn2+ plus YM101 therapy prolonged survival and inhibited tumor metastasis. a–b The overall survival curves of EMT-6-bearing and B16-bearing mice receiving the treatment of combination therapies or monotherapies. BALB/c mice were challenged with 3 × 105 EMT-6 cells on day 0. Therapy was initiated on day 2 (8 mice for each group). The survival status of mice was monitored for 45 days. C57BL/6 mice were subcutaneously inoculated with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (8 mice for each group). The survival status of mice was monitored for 4 weeks. c The representative images of lung tissues of mice receiving the treatment of combination therapies or monotherapies. C57BL/6 mice were intravenously injected with 2 × 105 B16 cells on day 0. Treatment was started on day 1 (8 mice for each group). 21 days after inoculation, the mice were euthanized, and the lung tissues were collected. d The number of B16 tumor nodules in lung tissues of mice receiving the treatment of combination therapies or monotherapies. e The weights of lung tissues of mice receiving the treatment of combination therapies or monotherapies. f The representative images of H&E staining of lung tissues of mice receiving the treatment of combination therapies or monotherapies. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatmentCC BY · PubMed Central
Fig. 5 Mn2+ plus YM101 therapy promoted the transformation from immune-excluded to immune-inflamed tumors and enhanced immune cell infiltration in the EMT-6 model. a The representative flow cytometry images of tumor-infiltrating CD8+ T cells. b The representative flow cytometry images of tumor-infiltrating natural killer cells (NKs). c The representative images of α-CD3 staining in the tumor periphery and the tumor center. d The quantitative analysis for T cell number by integral fluorescence intensity. e The quantitative analysis for the depth of T cell infiltration (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to Mn2+ plus YM101 therapy
Fig. 5 Mn2+ plus YM101 therapy promoted the transformation from immune-excluded to immune-inflamed tumors and enhanced immune cell infiltration in the EMT-6 model. a The representative flow cytometry images of tumor-infiltrating CD8+ T cells. b The representative flow cytometry images of tumor-infiltrating natural killer cells (NKs). c The representative images of α-CD3 staining in the tumor periphery and the tumor center. d The quantitative analysis for T cell number by integral fluorescence intensity. e The quantitative analysis for the depth of T cell infiltration (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to Mn2+ plus YM101 therapyCC BY · PubMed Central
Fig. 6 Flow cytometry and immunofluorescent staining assays to analyze the status of CD8+ tumor-infiltrating lymphocytes (TILs) in the B16 model. The representative images of tumor-infiltrating a CD8+ T cells, b Ki67+ CD8+ T cells, c Granzyme-B+ CD8+ T cells, d CD107a+ CD8+ T cells, e CD69+ CD8+ T cells, f CD25+ CD8+ T cells, and g CD44+ CD8+ T cells in flow cytometry assays. h The representative images of tumor-infiltrating CD4+ and CD8+ T cells in immunofluorescent staining assays (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatment
Fig. 6 Flow cytometry and immunofluorescent staining assays to analyze the status of CD8+ tumor-infiltrating lymphocytes (TILs) in the B16 model. The representative images of tumor-infiltrating a CD8+ T cells, b Ki67+ CD8+ T cells, c Granzyme-B+ CD8+ T cells, d CD107a+ CD8+ T cells, e CD69+ CD8+ T cells, f CD25+ CD8+ T cells, and g CD44+ CD8+ T cells in flow cytometry assays. h The representative images of tumor-infiltrating CD4+ and CD8+ T cells in immunofluorescent staining assays (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatmentCC BY · PubMed Central
Fig. 7 Flow cytometry assays to analyze the status of tumor-infiltrating natural killer cells (NKs) and dendritic cells (DCs) in the B16 model. The representative images of tumor-infiltrating a NKs, b Ki67+ NKs, c CD107a+ NKs, d TNF-α+ NKs, e Perforin+ NKs, and f DCs. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatment
Fig. 7 Flow cytometry assays to analyze the status of tumor-infiltrating natural killer cells (NKs) and dendritic cells (DCs) in the B16 model. The representative images of tumor-infiltrating a NKs, b Ki67+ NKs, c CD107a+ NKs, d TNF-α+ NKs, e Perforin+ NKs, and f DCs. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatmentCC BY · PubMed Central
Fig. 8 RNA-seq assay to investigate the immune profile of the B16 tumors. a The heatmap presenting the relative expression levels of differentially expressed genes (n = 4 biological replicates). b–e Gene set enrichment analysis (GSEA) showing the significantly enriched biological processes in Mn2+ plus YM101-treated tumors, relative to YM101-treated tumors. The biological processes including activation of immune response, activation of innate immune response, positive regulation of adaptive immune response, IFN-I production, IFN-I signaling pathway, response to IFN-I, T cell activation, NK activation, B cell activation, macrophage activation, myeloid dendritic cell activation, cell killing, T cell mediated cytotoxicity, NK mediated cytotoxicity, and antigen processing and presentation were significantly enriched in the combination group. f–k The scores of signatures of T cell, NK, dendritic cell (DC), macrophage, IFN-α response, and IFN-γ response. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatment
Fig. 8 RNA-seq assay to investigate the immune profile of the B16 tumors. a The heatmap presenting the relative expression levels of differentially expressed genes (n = 4 biological replicates). b–e Gene set enrichment analysis (GSEA) showing the significantly enriched biological processes in Mn2+ plus YM101-treated tumors, relative to YM101-treated tumors. The biological processes including activation of immune response, activation of innate immune response, positive regulation of adaptive immune response, IFN-I production, IFN-I signaling pathway, response to IFN-I, T cell activation, NK activation, B cell activation, macrophage activation, myeloid dendritic cell activation, cell killing, T cell mediated cytotoxicity, NK mediated cytotoxicity, and antigen processing and presentation were significantly enriched in the combination group. f–k The scores of signatures of T cell, NK, dendritic cell (DC), macrophage, IFN-α response, and IFN-γ response. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatmentCC BY · PubMed Central
Fig. 9 Immunofluorescent staining assays to measure the status of STING pathway, TGF-β signal, and epithelial-mesenchymal transition in the B16 model. The representative images of a α-p-TBK1 staining, b α-TGF-β1 staining, (c) α-SMA and α-Vimentin staining (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatment
Fig. 9 Immunofluorescent staining assays to measure the status of STING pathway, TGF-β signal, and epithelial-mesenchymal transition in the B16 model. The representative images of a α-p-TBK1 staining, b α-TGF-β1 staining, (c) α-SMA and α-Vimentin staining (n = 5 biological replicates). *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 denote the significant difference relative to combination treatmentCC BY · PubMed Central
Fig. 10 Schematic diagram showing the synergistic effect between Mn2+ and YM101. On the one hand, Mn2+ promoted dendritic cell (DC) maturation. On the other hand, YM101 restrained cancer-associated fibroblast (CAF) activity, enhanced T cell infiltration and restored T cell from exhaustion. The effects of Mn2+ and YM101 were independent and complementary, and the combination therapy had a potent and broad-spectrum antitumor effect
Fig. 10 Schematic diagram showing the synergistic effect between Mn2+ and YM101. On the one hand, Mn2+ promoted dendritic cell (DC) maturation. On the other hand, YM101 restrained cancer-associated fibroblast (CAF) activity, enhanced T cell infiltration and restored T cell from exhaustion. The effects of Mn2+ and YM101 were independent and complementary, and the combination therapy had a potent and broad-spectrum antitumor effectCC BY · PubMed Central

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Metadata

Authors
Yi, M., Niu, M., Zhang, J., Li, S., Zhu, S., Yan, Y., Li, N., Zhou, P., Chu, Q., & Wu, K.
Affiliations
  • Tongji Hospital (CN)
  • Wuhan YZY Biopharma (China) (CN)
  • Zhengzhou University (CN)
Corresponding author
Wu, Kongming
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2021-09-15
Volume
14
Issue
1
Pages
146-146
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-021-01155-6
PMC
PMC8442312
OpenAlex
W3200648346
Cited by
163
References
67
Citations by year
2026: 23 · 2025: 25 · 2024: 44 · 2023: 32 · 2022: 37 · 2021: 2
FWCI
10.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
national natural science foundation of china (82073370, 81874120)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
manganese, STING pathway, dendritic cell maturation, immune-excluded tumors, immunotherapy resistance, combination immunotherapy, tumor microenvironment, T cell activation, tumor-infiltrating lymphocytes, antitumor immunity, anti-PD-L1 resistance
MeSH terms
Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Animals, Drug Synergism, Humans, Immunotherapy, Manganese, Mice, Inbred BALB C, Neoplasms, Transforming Growth Factor beta, Antibodies, Bispecific, Cell Line, Tumor, Mice

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