Cross-Talk between Myeloid-Derived Suppressor Cells and Mast Cells Mediates Tumor-Specific Immunosuppression in Prostate Cancer

Abstract

Immunotherapy, including the use of checkpoint inhibitors, is a potent therapeutic approach for some cancers, but has limited success with prostate tumors, in which immune suppression is instigated by the tumor. The immunosuppressive capacity of mast cells, which promote adenocarcinoma development in the prostate, prompted our investigation on whether mast cells promote tolerance to SV40 Large-T antigen, the transforming oncogene in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. The incidence of adenocarcinoma was reduced in the offspring of a cross between TRAMP mice and mast cell-deficient Kit mice. TRAMP mice are tolerant to the SV40 Large T antigen, which is otherwise immunogenic in normal syngeneic B6 mice. Genetic ablation of mast cells in TRAMP mice restored their ability to mount a tumor-specific cytotoxic T-cell response. In Kit-TRAMP mice, the restored T-cell immunity correlated with the reduced activity of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), along with their reduced expression of ,, and Having found that CD40L-expressing mast cells can interact with CD40-expressing PMN-MDSC, we then determined that only Kit-TRAMP mice reconstituted with mast cells expressing CD40L could restore PMN-MDSCs suppressive functions, T-cell unresponsiveness and adenocarcinoma development. Thus, mast cells have an immunoregulatory effect on PMN-MDSCs activity through CD40L-CD40 interaction, favoring immunosuppression and tumor onset. In prostate cancer patients, analyses correlated poor clinical outcomes with high expression of genes related to mast cells and PMN-MDSCs..

Oxaliplatin regulates myeloid‐derived suppressor cell‐mediated immunosuppression via downregulation of nuclear factor‐κB signaling

“…Therefore, CD40 may be an immunosuppressive functional molecule on MDSCs. On the other hand, CD40L‐expressing mast cells could render CD40‐expressing PMN‐MDSCs immunosuppressive through CD40L/CD40 interaction in prostate cancer . This suggests that CD40 on MDSCs may be important for MDSCs becoming immunosuppressive cells.…”

“…On the other hand, CD40L-expressing mast cells could render CD40-expressing PMN-MDSCs immunosuppressive through CD40L/CD40 interaction in prostate cancer. 33 This suggests that CD40 on MDSCs may be important for MDSCs becoming immunosuppressive cells. Besides, it was reported that high level of CD40 expression on MDSCs correlated with upregulation of CXCR5 and promoted the recruitment of MDSCs to the cancer site.…”

Role of Mast Cells in the Control of Aldosterone Secretion

“…Especially, a growing body of evidence indicates that mast cells are implicated in tumor development [68][69][70][71][72][73]. Indeed, these cells are known to favor immunologic tolerance and secrete both growth and angiogenic factors which enhance tumor expansion [74][75][76]. Notably, a positive effect of mast cells has been observed on growth of endocrine neoplasias, including neuroendocrine tumors of thyroid, pancreas, and adrenal (pheochromocytomas) [77][78][79].…”

Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation

“…It is reported that mast cells not only induce the recruitment but also promote the suppressive function of MDSCs, probably through CD40L-CD40 interaction (219,220).…”