Synergy of heterodimeric IL-15 immunotherapy and a Fatty Acid Metabolism Modulator enhances intratumoral lymphocyte metabolism and eradicates EO771 murine breast tumors

Abstract Tumor-infiltrating cytotoxic CD8 +T cells frequently acquire an altered state of differentiation referred to as “exhaustion”, which prevents control tumor growth. We study hetIL-15, a cytokine that stimulates the generation, proliferation and function NK cells. The objectives this was assess effects hetIL-15 immunotherapy in TNBC tumors, evaluate metabolic profile tumor-infiltrating T any potential synergy with Fatty Acid Metabolism Modulator (FAMM). Using EO771 orthotopic breast cancer model we monitored efficacy locoregional administration combination FAMM. effect treatment on growth, survival mice status immune using Seahorse flow cytometry. resulted complete regression 40% treated animals increased survival. infiltrating were tumors showed enhanced activation proliferation. Their flux analysis confirmed robust rise Oxygen Consumption Rate (OCR) substantial increase spare respiratory capacity. Combined FAMM mitochondrial function, FA uptake OCR. In addition, therapy statistically significant growth delay eradication 85% mice. Our results indicate reprogramming tumor-specific might represent strategy promote metabolically hostile Tumor Microenvironment (TME), enhancing clinical immunotherapy.