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Increased tumor-infiltrating CD45RA^-CCR7^- regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress.

ABSTRACT: Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA^-CCR7^- Treg subset constituted most tumor-infiltrating Tregs. Tumor-infiltrating CD45RA^-CCR7^- Treg subset with an effector/memory phenotype accumulated in tumors and expressed low level of HLA-DR. Gastric tumor-derived TNF-? induced CD45RA^-CCR7^- Treg subset with similar phenotype to their status in tumors and inhibited their HLA-DR expression via activating STAT3 phosphorylation. These tumor-associated CD45RA^-CCR7^- Treg subset exerted superior immunosuppressive properties to effectively suppress CD8⁺ T cells' anti-tumor function including CD8⁺ T-cell IFN-? and granzyme B (GrB) production as well as CD8⁺ T-cell proliferation in vitro, and also contributed to the growth and progression of human gastric tumors in vivo, via IL-10 secretion and cell-cell contact mechanisms. Moreover, increased tumor-infiltrating CD45RA^-CCR7^- Treg subset as well as higher intratumoral CD45RA^-CCR7^- Treg/CD8⁺ T-cell ratio was associated with advanced disease progression and reduced GC patient survival. This study therefore identifies a novel immunosuppressive pathway involving CD45RA^-CCR7^- Treg subset development within the GC microenvironment. Efforts to inhibit this pathway may therefore prove a valuable strategy to prevent, and to treat this immune suppressive of GC.

SUBMITTER: Mao FY

PROVIDER: S-EPMC5596574 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Increased tumor-infiltrating CD45RA-CCR7- regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress.

Mao Fang-Yuan FY Kong Hui H Zhao Yong-Liang YL Peng Liu-Sheng LS Chen Weisan W Zhang Jin-Yu JY Cheng Ping P Wang Ting-Ting TT Lv Yi-Pin YP Teng Yong-Sheng YS Fu Xiao-Long XL Liu Yu-Gang YG Wu Xiao-Long XL Hao Chuan-Jie CJ You Nan N Luo Ping P Yu Pei-Wu PW Zou Quan-Ming QM Guo Gang G Zhuang Yuan Y

Cell death & disease 20170817 8

Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA-CCR7- Treg subset constituted most tumor-infiltrating Tregs. Tumor-infiltrating CD45RA-CCR7- Treg subset ...[more]

PMID: 28817117

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Project description:BACKGROUND:Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. METHODS:Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. RESULTS:Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. CONCLUSION:Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.

Dataset Information

Increased tumor-infiltrating CD45RA^-CCR7^- regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress.

Publications

Increased tumor-infiltrating CD45RA<sup>-</sup>CCR7<sup>-</sup> regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress.

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