Post-operative IL-15 enhances the immunosuppressive effects of myeloid derived suppressor cells in sarcoma 2258326

Abstract

Abstract Introduction Myeloid derived suppressor cells (MDSCs) inhibit NK and T cells leading to negative outcomes in cancer. Interleukin 15 (IL-15) is a stimulatory cytokine with anti-tumor activity that is limited by systemic toxicity. We have previously shown clinical benefit of IL-15 in dogs with metastatic osteosarcoma. We recently reported results of a phase II canine oncology trial of inhaled IL-15 after surgery for primary osteosarcoma demonstrating paradoxically worse outcomes with IL-15. Here, we sought to evaluate the effects of post-operative IL-15 on MDSC phenotype and function in dog and mouse sarcoma. Methods We performed single cell RNA sequencing of peripheral blood mononuclear cells from dogs with osteosarcoma treated with surgery and IL-15. Immune populations were identified and MDSC frequencies and gene expression were compared before and after surgery. C57BL/6 mice underwent excision of syngeneic fibrosarcoma flank tumors and received post-operative IL-15. Splenic MDSCs were co-cultured with naïve wild type splenocytes stimulated with anti-CD3:CD28. MDSC phenotype and T cell proliferation were evaluated by flow cytometry. Results MDSC frequencies and IL-15 receptor alpha (IL-15RA) expression were enriched in dogs after surgery. In mice, surgery increased MDSC frequencies, IL-15RA expression, and CD155 expression. Post-operative IL-15 increased PD-L1 and arginase expression on intratumoral MDSCs. Surgery increased MDSC suppression across multiple suppressor:responder ratios, and post-operative IL-15 further increased MDSC suppression. Conclusion In canine patients and mouse sarcoma models, surgery increased MDSC frequencies and IL-15RA expression, and post-operative IL-15 increased MDSC suppressive phenotype and function. These findings suggest surgery may limit the anti-tumor benefit of IL-15 in the post-operative setting. As surgery remains the cornerstone of treatment for sarcoma, targeting MDSCs in the setting of post-operative IL-15 immunotherapy is likely to have high translational impact. Funding Source NIH 1T32CA251007, UC Cancer Research Coordinating Committee Grant, National Leiomyosarcoma Foundation Grant Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)