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

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.