Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway

Journal for ImmunoTherapy of Cancer

Qiang Ma¹  Bin Han¹  Jun Chen²  Yongliang Zhao²  Xianhua Wang³  Weisan Chen⁴  Tingting Wang⁵  Hui Kong⁵  Yuan Zhuang⁵  Fangyuan Mao⁵  Yipin Lv⁵  Ping Cheng⁵  Yongsheng Teng⁵  Quanming Zou⁵  Yugang Liu⁵  Na Chen⁵  Chuanjie Hao⁵  Jinyu Zhang⁵  Liusheng Peng⁵ 

[1] Affiliated Hospital of North Sichuan Medical College;Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University;Department of Obstetrics and Gynecology, Research Institute of Surgery, Daping Hospital, Third Military Medical University;La Trobe Institute of Molecular Science, School of Molecular Science, La Trobe University;National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University;

关键词: Gastric cancer;    Tumor microenvironment;    Mast cells;    TNF-α;    PD-L1;    Immunotherapy;   

DOI  :  10.1186/s40425-019-0530-3

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown