Peroxisome Biogenesis in Anti-Tumor T Tell Metabolic Fitness

ABSTRACT Cancer remains a leading cause of mortality globally, particularly among aging populations. While adoptive T cell transfer therapy (ACT) has shown promise in treating hematological malignancies, its efficacy against solid tumors is hindered by tumor-induced immunosuppression. A significant contributor to the failure of ACT is the exhaustion and dysfunction of T cells upon exposure to the hypoxic and lipid-rich tumor microenvironment (TME). Peroxisomes, organelles involved in regulating fatty acids and reactive oxygen species, have been implicated in cellular functions, yet their role in anti-tumor T cell responses within the TME remains poorly understood. Our preliminary data shows a reduction in peroxisome levels and antioxidant enzyme catalase in T cells exposed to the TME, correlating with increased exhaustion markers, suggesting peroxisome deficiency may be limiting T cells ability to overcome TME oxidative stress. The overarching goal of this study is to elucidate the impact of peroxisome biogenesis on adaptive immune responses, particularly within the TME and anti-tumor immunity. We hypothesize that T cells with enhanced peroxisome capacity will exhibit increased antioxidant defenses and improved interactions with other organelles, thereby enhancing their resistance to lipid-mediated stress and persistence within the immunosuppressive TME. This hypothesis will be tested through two integrative specific aims. Specific Aim 1 aims to delineate the mechanisms by which peroxisome capacity influences T cell exhaustion, lipid accumulation, and organelle interactions. We anticipate that T cells with elevated peroxisome levels will demonstrate enhanced anti-tumor activity through regulation of catalase and lipid intermediates, and by maintaining interactions with key organelles to mitigate oxidative stress and lipid peroxidation. Specific Aim 2 seeks to establish optimal in vivo conditions for promoting peroxisome capacity to generate exhaustive-resistant anti-tumor T cells. We expect that enhancing peroxisome capacity will improve T cell persistence and mitigate exhaustion in the TME. This will be investigated through ACT experiments using melanoma and Burkitt lymphoma models, employing strategies to augment peroxisome quantity and catalase levels. The findings from this study will provide novel insights into the role of peroxisomes in modulating T cell function and anti-tumor immunity. By uncovering mechanisms to enhance ACT efficacy through peroxisome manipulation, this research holds translational potential for improving cancer immunotherapy strategies beyond ACT, including immune checkpoint blockade therapy.