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

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.

SUBMITTER: Lv Y

PROVIDER: S-EPMC6390584 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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

Lv Yipin Y Zhao Yongliang Y Wang Xianhua X Chen Na N Mao Fangyuan F Teng Yongsheng Y Wang Tingting T Peng Liusheng L Zhang Jinyu J Cheng Ping P Liu Yugang Y Kong Hui H Chen Weisan W Hao Chuanjie C Han Bin B Ma Qiang Q Zou Quanming Q Chen Jun J Zhuang Yuan Y

Journal for immunotherapy of cancer 20190226 1

<h4>Background</h4>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.<h4>Methods</h4>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 C ...[more]

PMID: 30808413

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Project description:Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-β, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1.

Project description:BackgroundMyeloid-derived suppressor cells (MDSCs) are the major factor in gastric cancer (GC) immune evasion. Nevertheless, the molecular process underlying the expansion of MDSCs induced by tumor-derived exosomes (TDEs) remains elusive.MethodsThe levels of exosomal and soluble PD-L1 in ninety GC patients were examined via enzyme-linked immunosorbent assay (ELISA) to determine their prognostic value. To investigate the correlation between exosomal PD-L1 and MDSCs, the percentage of MDSCs in the peripheral blood of 57 GC patients was assessed via flow cytometry. Through ultracentrifugation, the exosomes were separated from the GC cell supernatant and detected via Western blotting, nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). The function of exosomal PD-L1 in MDSCs was evaluated via immunofluorescence, Western blotting and flow cytometry in a GC cell-derived xenograft (CDX) model.ResultsThe overall survival (OS) of GC patients in the high exosomal PD-L1 group was significantly lower than that of patients in the low exosomal PD-L1 group (P = 0.0042); however, there was no significant correlation between soluble PD-L1 and OS in GC patients (P = 0.0501). Furthermore, we found that the expression of exosomal PD-L1 was positively correlated with the proportions of polymorphonuclear MDSCs (PMN-MDSCs, r = 0.4944, P < 0.001) and monocytic MDSCs (M-MDSCs, r = 0.3663, P = 0.005) in GC patients, indicating that exosomal PD-L1 might induce immune suppression by promoting the aggregation of MDSCs. In addition, we found that exosomal PD-L1 might stimulate MDSC proliferation by triggering the IL-6/STAT3 signaling pathway in vitro. The CDX model confirmed that exosomal PD-L1 could stimulate tumor development and MDSC amplification.ConclusionsExosomal PD-L1 has the potential to become a prognostic and diagnostic biomarker for GC patients. Mechanistically, MDSCs can be activated by exosomal PD-L1 through IL-6/STAT3 signaling and provide a new strategy against GC through the use of exosomal PD-L1 as a treatment target.

Dataset Information

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

Publications

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

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