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

Elena Jachetti,Claudia Enriquez,Valeria Cancila,Paola Ostano,Mario P Colombo,Claudia Chiodoni,Sabina Sangaletti,Alice Rigoni,Claudio Tripodo,Barbara Frossi,Giovanna Chiorino,Patrizia Casalini,Beatrice Belmonte,Barbara Cappetti,Carlo E Pucillo,Lucia Bongiovanni

doi:10.1158/2326-6066.cir-17-0385

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 KitWsh 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 KitWsh-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 Arg1, Nos2, and Stat3 Having found that CD40L-expressing mast cells can interact in vivo with CD40-expressing PMN-MDSC, we then determined that only KitWsh-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, in silico analyses correlated poor clinical outcomes with high expression of genes related to mast cells and PMN-MDSCs. Cancer Immunol Res; 6(5); 552-65. ©2018 AACR.

Highlights

Prostate cancer is a leading cause of cancer death worldwide [1]
We have shown that pharmacologic inhibition of mast cells degranulation in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice reduces incidence and slows progression of prostate adenocarcinoma, but favors prostate tumors with neuroendocrine features [9, 10]
To exclude the possibility that increased antitumor immune response in KitWsh-TRAMP mice could have been due to altered Tcell frequency or distribution, we evaluated by flow cytometry the percentages of T lymphocytes in spleens and prostates of TRAMP, KitWsh-TRAMP, KitWsh-TRAMP mice reconstituted with bone marrow–derived mast cells (BMMC) and their nononcogenic littermates (Supplementary Fig. S4)

Summary

Introduction

Prostate cancer is a leading cause of cancer death worldwide [1]. surgery and radiotherapy are effective for localized disease, advanced or recurrent disease treated with androgen ablation often develops into castration-resistant and metastatic disease with fatal outcomes [2].Immunotherapy and immune checkpoint inhibitors have been tested with success in several clinical trials treating melanoma, non–small cell lung cancer, and renal cell carcinoma [3], but with little success in treating prostate cancer [2]. Mast cells mediate immunologic tolerance in several disease models, including cancer [11], possibly through interaction with other immune suppressive cell populations such as Tregs [12] and myeloid-derived suppressor cells To study the contribution of mast cells to immunosuppression during prostate adenocarcinoma development, we used the TRAMP mouse model, in which prostate epithelium transforms because of the SV40 early genes [small and large T antigens (Tag)] driven by the androgen-responsive rat probasin regulatory element.

Methods

Results

Conclusion