Abstract 6523: TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments

Abstract

Abstract Frequency and function of CD8+ tumor-infiltrating T cells (TILs) decide on clinical outcome of cancer immunotherapy; and TOX function as a crucial regulator of TIL dysfunction. In the present study, we found that multiplex factors, such as tumor cell, viral antigens and hypoxia, in tumor microenvironments (TME) induced CD8+ TIL ferroptosis by upregulating TOX. Single cell RNA-sequencing revealed that TOX modulated Havcr2, Pdcd1, Hmox1, Gpx4, and Ctsb transcription in human and murine CD8+ TILs. We further generated TOX conditional knockout in CD8+ T cell (Toxflox/floxCd8Cre, CKO) mice and the tumor-bearing CKO mice exhibited increased anti-tumor immunity and survival time. TOX upregulation increased reactive oxygen species (ROS), lipid peroxidation, and ferrous iron, leading to a GPX4-dependent CD8+ T cell ferroptosis. Genetic or antibody ablation of TOX, TIM-3, or HO-1 indicated that these molecules orchestrated CD8+ TIL ferroptosis by inducing iron overload and lipid peroxidation. Targeting TOX, PD-1, TIM-3, or ferroptosis boosted the anti-tumor suppression of tumor-specific T cell-based adoptive cell therapy (ACT) in murine tumor model. TOX, TIM-3 and GPX4 were prognostic predictors in human cervical cancer. This finding identifies a novel mechanism of tumor-induced CD8+ T cell ferroptosis underwent by TOX that provides new insights in improving TIL-based ACT immunotherapy. Key words: TOX, CD8+ T cells, ferroptosis, tumor microenvironments, cancer immunotherapy Citation Format: Jiang Li, Qian Zhu, Xiufeng Liu. TOX upregulation promotes a GPX4-dependent CD8+ T cell ferroptosis in tumor microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6523.