Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8<sup>+</sup> T cell response in esophageal squamous cell carcinoma

Chen, Xinfeng; Wang, Liping; Li, Pupu; Song, Mengjia; Qin, Guohui; Gao, Qun; Zhang, Zhen; Yue, Dongli; Wang, Dan; Nan, Shufeng; Qi, Yu; Li, Feng; Li, Yang; Huang, Lan; Zhang, Mingzhi; Zhang, Bin; Gao, Yanfeng; Zhang, Yi

doi:10.1002/ijc.31730

Cited by 70 publications

(58 citation statements)

References 49 publications

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“…Similarly, the combination of TGFb and PD-L1 inhibition greatly enhanced antitumor immune function (20). In addition, concomitant TGFb/PD-L1 pathway inhibition greatly enhanced T-cell responses in esophageal squamous cell carcinoma (21), and blockade of greatly sensitized genetically reconstituted models of colon cancer metastasis (22). Further, TGFb pathway inhibitors enhanced responsiveness to PD-1/PD-L1-neutralizing antibodies in mice bearing poorly immunogenic 4T1-LP breast tumors (23).…”

Section: Discussionmentioning

confidence: 99%

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

Principe

Park

Dorman

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of 8%. This is mainly attributed to the late stage of presentation, as well as widespread resistance to conventional therapy. In addition, PDAC tumors are largely nonimmunogenic, and most patients have displayed incomplete responses to cancer immunotherapies. Our group has previously identified TGFb as a crucial repressor of antitumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes. However, pharmacologic inhibition of TGFb signaling has had limited efficacy in clinical trials, failing to promote a significant antitumor immune response. Hence, in this work, we extend our analysis to identify and circumvent the mechanisms of resistance to TGFb signal inhibition in PDAC. Consistent with our previous observations, adoptive transfer of TGFb-insensitive CD8 þ T cells led to the near complete regression of neoplastic disease in vivo. However, we demonstrate that this cannot be recapitulated via global reduction in TGFb signaling, through either genetic ablation or pharmacologic inhibition of TGFBR1. In fact, tumors with TGFb signal inhibition displayed increased PD-L1 expression and had no observable change in antitumor immunity. Using genetic models of advanced PDAC, we then determined that concomitant inhibition of both TGFb and PD-L1 receptors led to a reduction in the neoplastic phenotype, improving survival and reducing disease-associated morbidity in vivo. Combined, these data strongly suggest that TGFb and PD-L1 pathway inhibitors may synergize in PDAC, and this approach warrants clinical consideration. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussionmentioning

confidence: 99%

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

Principe

Park

Dorman

et al. 2019

Molecular Cancer Therapeutics

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“…MDSCs can inhibit CD8 + T cells in esophageal squamous cell carcinoma. 8 Here, perforin, granzyme B and proliferation decreased and the early apoptosis of CD8 + T cells increased after CD8 + T cells from controls were co-cultured with MDSCs. These data implied that MDSCs with excessive Gal-9 might induce TIM3 overexpression in CD8 + T cells, leading to a downward trend of perforin and granzyme B after CD8 + T cells from MDS were co-cultured with MDSCs.…”

Section: Discussionmentioning

confidence: 77%

“…Perforin and granzyme B are the most important cytokines in CD8 + T cells against infectious and malignant cells. MDSCs can inhibit CD8 + T cells in esophageal squamous cell carcinoma . Here, perforin, granzyme B and proliferation decreased and the early apoptosis of CD8 + T cells increased after CD8 + T cells from controls were co‐cultured with MDSCs.…”

Section: Discussionmentioning

confidence: 92%

“…6 Adoptive T cell immunotherapy in neoplastic disorders has been restricted by CD8 + T cells 'exhaustion' due to some immune checkpoint inhibitors, such as T cell immunoglobulin and mucin domain 3 (TIM3), programmed death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG3). 7,8 Among these immune checkpoints, the interaction of TIM3 with its ligand galectin-9 (Gal-9) promotes Tc1 cells 9 apoptosis, CD8 + T cells exhaustion, 10,11 malignant cell proliferation 12 and myeloid-derived suppressor cells (MDSCs) amplification. 13 In humans, MDSCs are usually defined as CD14 − CD11b + cells or the cells which express the myeloid marker (CD33) and are lack of lineage maturation markers and HLA-DR 14 (Lin − HLA-DR − CD33 + cells).…”

Section: Introductionmentioning

confidence: 99%

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CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

Tao

Han

Gao

et al. 2019

J Cellular Molecular Medi

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CD8+ T cells play a central role in antitumour immunity, which often exhibit ‘exhaustion’ in the setting of malignancy and chronic viral infection due to T cell immunoglobulin and mucin domain 3 (TIM3) and myeloid‐derived suppressor cells (MDSCs). Our team previously found that overactive MDSCs and exhausted TIM3+CD8+ T cells were observed in myelodysplastic syndromes (MDS) patients. However, it is not obvious whether MDSCs suppress CD8+ T cells through TIM3/Gal‐9 pathway. Here, Gal‐9, as the ligand of TIM3, was overexpressed in MDSCs. The levels of Gal‐9 in bone marrow supernatants, serum and culture supernatants of MDSCs from MDS patients were elevated. CD8+ T cells from MDS or normal controls produced less perforin and granzyme B and exhibited increased early apoptosis after co‐culture with MDSCs from MDS. Meanwhile, the cytokines produced by CD8+ T cells could be partially restored by TIM3/Gal‐9 pathway inhibitors. Furthermore, CD8+ T cells produced less perforin and granzyme B after co‐culture with excess exogenous Gal‐9, and the function of CD8+ T cells was similarly restored by TIM3/Gal‐9 pathway inhibitors. Expression of Notch1, EOMES (associated with perforin and granzyme B secretion), p‐mTOR and p‐AKT (associated with cell proliferation) was decreased in CD8+ T cells from MDS after co‐culture with excess exogenous Gal‐9. These suggested that MDSCs might be the donor of Gal‐9, and TIM3/Gal‐9 pathway might be involved in CD8+ T cells exhaustion in MDS, and that TIM3/Gal‐9 pathway inhibitor might be the promising candidate for target therapy of MDS in the future.

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“…Furthermore, MDCSs induce NK cells anergy through the membrane-bound TGFβ (92). Interestingly, TGF-β-produced by MDSCs promotes the expression of programmed cell death-1 (PD1) in T cells (93). Similarly, MDSCs can hinder T cell fitness and function by directly binding FASL and PDL1 with respective death receptor ligands expressed on T cell surface (94,95).…”

Section: Mdscs Promote Primary Tumor Growth and Local Invasionmentioning

confidence: 99%

The Engagement Between MDSCs and Metastases: Partners in Crime

et al. 2020

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Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed "pre-metastatic niche" (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically reprogram not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an "emergency" myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.

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Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8⁺ T cell response in esophageal squamous cell carcinoma

Cited by 70 publications

References 49 publications

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

The Engagement Between MDSCs and Metastases: Partners in Crime

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Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8+ T cell response in esophageal squamous cell carcinoma

Cited by 70 publications

References 49 publications

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

CD8+ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway

The Engagement Between MDSCs and Metastases: Partners in Crime

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Dual TGF‐β and PD‐1 blockade synergistically enhances MAGE‐A3‐specific CD8⁺ T cell response in esophageal squamous cell carcinoma

CD8⁺ T cells exhaustion induced by myeloid‐derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal‐9 pathway