Abstract A061: Discovery of resilient T cells from patients in responses to combination immunotherapy and their metabolic features

Abstract Salvage combination therapy including radiotherapy and immunotherapy has been used to reduce tumor burden and tumor-related symptoms in patients with advanced cancer that is refractory to ICI monotherapy. Among those patients who experienced significant tumor regression in responses to combination therapy, we identified a rebound of effector CD8+ T cells with high cytotoxic capacity and metabolic fitness. We use the term T cell resilience to explain the rebound of cytotoxic CD8+ T cells in response to combination therapy and examine the underlying mechanisms of T cell resilience. Resilient T cells are enriched in CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). We found ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. Importantly, ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers and improve the efficacy of tumor-infiltrating lymphocytes (TIL) therapy in animal models. Our results demonstrate the presence of resilient T cells in patients, suggest that T cell resiliency is attributed to their metabolic reprogram mediated by ME1, which is a new T cell-intrinsic therapeutic target for T cell-based immunotherapy. Citation Format: Haidong Dong, Joanina K Gicobi. Discovery of resilient T cells from patients in responses to combination immunotherapy and their metabolic features [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A061.