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

Immunotherapy, including the use of checkpoint inhibitors, isa potent therapeutic approach for some cancers, but has limitedsuccess with prostate tumors, in which immune suppression isinstigated by the tumor. The immunosuppressive capacity of mastcells, which promote adenocarcinoma development in the prostate,prompted our investigation on whether mast cells promotetolerance to SV40 Large-T antigen, the transforming oncogene intransgenic adenocarcinoma of the mouse prostate (TRAMP) mice.The incidence of adenocarcinoma was reduced in the offspringof a cross between TRAMP mice and mast cell–deficient KitWshmice. TRAMP mice are tolerant to the SV40 Large T antigen, whichis otherwise immunogenic in normal syngeneic B6 mice. Geneticablation of mast cells in TRAMP mice restored their ability tomount a tumor-specific cytotoxic T-cell response. In KitWshTRAMPmice, the restored T-cell immunity correlated with thereduced activity of polymorphonuclear myeloid-derived suppressorcells (PMN-MDSC), along with their reduced expression ofArg1, Nos2, and Stat3. Having found that CD40L-expressing mastcells can interact in vivo with CD40-expressing PMN-MDSC, wethen determined that only KitWsh-TRAMP mice reconstituted withmast cells expressing CD40L could restore PMN-MDSCs suppressivefunctions, T-cell unresponsiveness and adenocarcinomadevelopment. Thus, mast cells have an immunoregulatory effecton PMN-MDSCs activity through CD40L-CD40 interaction,favoring immunosuppression and tumor onset. In prostate cancerpatients, in silico analyses correlated poor clinical outcomes withhigh expression of genes related to mast cells and PMN-MDSCs.Cancer Immunol Res; 6(5); 552–65. 2018 AACR