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The file contains the list and information of all antibodies used in the study

Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell response in TRAMP and KitWsh-TRAMP mice. Supplementary Figure 2. CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice are responsive. Supplementary Figure 3. Quantification of MCs or T cells after reconstitution of depletion, respectively. Supplementary Figure 4. Flow cytometry identification of T cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 5. Flow cytometry identification of myeloid cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 6. MCs and PMN-MDSC can interact via CD40L-CD40 in TRAMP mice. Supplementary Figure 7. Wild type and CD40L-/- BMMC are equally functional, but CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice reconstituted with BMMC CD40L-/- are still responsive. Supplementary Figure 8. MCs, CD40L and CD33 co-localize in human tumor prostate cancer samples. Supplementary Figure 9. Correlation between MC-genes and MDSC-activity genes in human prostate cancer data sets. Supplementary Figure 10. MC/PMN-MDSC signatures outperform random signatures of the same length.

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.

Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cell-to-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b+Gr1+ immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleen-derived monocytic MDSCs, through a mechanism involving IFNγ and nitric oxide production. In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth. In light of these results, interfering with the MDSC:mast cell axis could be a promising approach to abrogate MDSC-related immune suppression and to improve the antitumor immune response. Cancer Immunol Res; 3(1); 85–95. ©2014 AACR.

IFN- γ role in the regulation of M-MDSC:MC suppressive axis.

Supplemental material and figure legend

MDSC accumulation in CT-26 tumor bearing mice and migration in response to mast cells and to conditioned media from colon cancer cell line.