Interleukin 15 stimulation augments myeloid-derived suppressor cell immunosuppression in cross-species models of sarcoma 2220048

Abstract

Abstract Introduction Myeloid-derived suppressor cells (MDSCs) are a heterogenous immune cell population expanded in cancer, with immunosuppressive effects on natural killer (NK) and T cells, inhibiting antitumor immunity. Cytokine immunotherapy with interleukin 15 (IL-15) has shown promise in canine and human sarcomas. Although IL-15 is classically associated with heightened NK and T cell antitumor response, MDSC expression of IL-15 receptor alpha (IL-15Rα) may be associated with shorter disease-free intervals in dogs receiving IL-15 for osteosarcoma (OSA). We sought to characterize the effects of pre-conditioning MDSCs in vitro with IL-15 in cross-species models. Methods Murine MDSCs (CD11b+ Gr1+) were isolated from OSA-bearing BALB/c spleens, pre-treated +/- IL-15, and cultured with wild type splenocytes (anti-CD3/28 stimulated), then evaluated by flow cytometry. Human MDSCs were differentiated in vitro from CD33+ PBMCs with IL-6 and GM-CSF, then pre-treated +/- IL-15 and TTI-101 (STAT3 inhibitor). MDSCs were cultured with donor-matched CD33- PBMCs (anti-CD3/28 and IL-2 stimulated), then evaluated by flow cytometry. Results IL-15 pre-treatment increased the suppressive effects of murine MDSCs on wild type splenic CD8 T cell and NK cell proliferation after in vitro stimulation. IL-15 pre-treatment increased the suppressive effects of human MDSCs on T cell (CD4 and CD8) and NK cell proliferation and cytotoxicity. Pre-treatment with TTI-101 reduced the IL-15-induced increase in suppressive effects of MDSCs. Conclusion The IL-15/IL-15Rα axis appears to regulate MDSC function with potential pro-tumor effects. Better understanding of this pathway is likely to have translational impact in cancer and autoimmunity. Funding Source NIH Training Grant T32GM136559, UC Davis Center for Companion Animal Health Endowment Funds Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)