Abstract 5082: Heterodimeric IL-15 (hetIL-15) immunotherapy synergizes with Fatty Acid Metabolism Modulator (FAMM) to eradicate TNBC EO771 murine tumors

Abstract Introduction: Metabolic fitness and T cell survival are crucial in anti-tumor responses because nutrients are often scarce and other regulatory molecules may be unfavorable in the tumor microenvironment leading to T cell dysfunction, stress, and apoptosis. Tumor-infiltrating cytotoxic CD8+T cells frequently acquire an altered state of differentiation referred to as “exhaustion” and, as a result, they fail to control tumor outgrowth. IL-15 cytokine stimulates the generation, proliferation and cytotoxic function of tumor specific CD8+ T cells and NK cells. The objective of this study was to assess the effects of hetIL-15 immunotherapy in triple negative breast cancer tumors (TNBC), to evaluate the metabolic profile of the tumor-infiltrating T cells and to study any potential synergy using a Fatty Acid Metabolism Modulator (FAMM) to enhance T cell metabolism. Study design and methods: We used the murine EO771 orthotopic breast cancer model to study the efficacy of locoregional administration of hetIL-15 immunotherapy in combination with a FAMM. We monitored the effect of treatment on number, metabolism and mitochondrial function of the tumor-infiltrating immune cells by flow cytometry, Seahorse flux analysis and Mitotracker, 2-NBDG and/or Bodipy staining. Results: hetIL-15 locoregional administration, as as single agent, resulted in complete regression in 40% of the treated animals and increased survival. Tumor-infiltrating cytotoxic CD8+T and NK cells increased in hetIL-15 treated tumors and showed enhanced activation and proliferation. Metabolic flux analysis of the tumor-infiltrating cytotoxic CD8+T cells from hetIL-15-treated mice confirmed a rise in oxygen consumption rate (OCR) with substantial increase of spare respiratory capacity, which supports an activated/non exhausted phenotype of these hetIL-15 treated effector cells. Since, further promoting fatty acid (FA) catabolism improves the tumor-infiltrated CD8+T cells’s ability to slow tumor progression, we combined hetIL-15 immunotherapy with a FAMM. Combination therapy resulted in increased mitochondrial function, FA uptake and OCR, revealing a more metabolically active phenotype compared to the tumor-infiltrating CD8+T cells from hetIL-15 monotherapy group. In addition, combined treatment of IL-15 immunotherapy and FAMM resulted in statistically significant EO771 tumor growth delay and complete eradication of the tumors in 85% of mice. Conclusions: Our results indicate that hetIL-15 synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and complete cures. We suggest that metabolic reprogramming of tumor-specific CD8+Tcells might represent a strategy to promote survival in the metabolically hostile TME as part of an approach to enhance the clinical efficacy of immunotherapy. Citation Format: Sevasti Karaliota, Dimitris Stellas, Vasiliki Stravokefalou, Breana Myers, Barbara K. Felber, George N. Pavlakis. Heterodimeric IL-15 (hetIL-15) immunotherapy synergizes with Fatty Acid Metabolism Modulator (FAMM) to eradicate TNBC EO771 murine tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5082.