Heterodimeric Il-15 (Hetil-15) Affects Conventional Dendritic Cells And A Distinct Novel Dendritic Cell Population In Different Mouse Cancer Models Of Breast And Pancreatic Cancer.

Abstract Introduction: IL-15 is a cytokine inducing proliferation and cytotoxic function of lymphocytes, including CD8+ T and NKs cells. We have produced the native heterodimeric form of IL-15 (hetIL-15) which has advanced in clinical trials due to its anticancer activities in many different mouse cancer models. The objective of this study was to explore how hetIL-15 affects lymphoid and myeloid cell populations in the tumor microenvironment in different mouse cancer models of breast and pancreatic cancer. Study Design and Methods: We studied the therapeutic efficacy of intraperitoneal or locoregional administration of hetIL-15 in three different orthotopic mouse cancer models. We employed 4T1 and EO771 breast cancer models, which mimic human triple negative breast cancer and a KPC derived pancreatic cancer model. hetIL-15 effects on tumor infiltrating immune cells were evaluated by flow cytometry and immunohistochemistry. Results: hetIL-15 treatment showed a profound effect on the EO771 breast cancer model resulting in complete tumor regression in ~40% of the treated mice. Additionally, hetIL-15 caused tumor delay in 4T1 and KPC derived cancer models. Flow cytometry analysis revealed an increase of cytotoxic effector cells, and especially CD8+ T cells, with enhanced cytotoxic activity and proliferation in all cancer models tested. Immunohistochemistry verified the accumulation of cytotoxic effector cells intratumorally upon hetIL-15 treatment. Furthermore, flow analysis showed an increase of infiltrating conventional type 1 dendritic cells (cDC1s) which was found only in EO771 breast tumors. On the contrary, 4T1 breast and KPC derived pancreatic tumors, but not EO771 tumors, displayed an accumulation of infiltrating conventional type 2 dendritic cells (cDC2s). Importantly, the flow cytometry analysis revealed yet additional novel distinct dendritic cell population characterized by CD103intCD11b+ immunophenotype, which was mostly evident in tumor tissues treated with hetIL-15 in all three models. Phenotypic profiling of this novel DC population identified expression of several cDC1 specific markers, including CD103, IRF8 and XCR1. Both cDC1s and the novel DC population were inversely correlated with the tumor size in EO771 breast cancer model. Conclusions: hetIL-15 affects both T cells and conventional dendritic cells in syngeneic murine cancer models of breast and pancreatic cancer. We report that the treatment with hetIL-15 increases a novel distinct dendritic cell population (CD103intCD11b+) in all three models. Since we have previously reported that hetIL-15 induces long term immunological protection from tumor rechallenge, these findings suggest hetIL-15 as a promising therapeutic agent in treatment of triple negative breast and pancreatic cancer. Citation Format: Vasiliki Stravokefalou, Dimitris Stellas, Sevasti Karaliota, Bethany Nagy, Theresa Guerin, Serguei Kozlov, Barbara K. Felber, George N. Pavlakis. Heterodimeric IL-15 (hetIL-15) affects conventional dendritic cells and a distinct novel dendritic cell population in different mouse cancer models of breast and pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2727.