Metabolic regulation of anti-tumor CD8+ T cell responses

Abstract

Cancer immunotherapies have revolutionized the cancer therapy landscape, but many patients do not yet benefit. Methods to increase the applicability and response rates of cancer immunotherapy are therefore warranted. CD8+ T cells are key effectors of the anti-tumor immune response, but their function is often hampered in cancer. Both systemic metabolic conditions, such as aging and obesity, and tumor-specific metabolic barriers impair the anti-tumor T cell response. To identify distinct cell-intrinsic metabolic vulnerabilities of CD8+ T cells and cancer cells, aiming to enable the specific therapeutic targeting of either population, we conducted an in vitro pharmacologic screen. We found that CD8+ T cells are highly sensitive to ferroptosis, a lipid peroxidation-triggered cell death pathway, induced by inhibitors of glutathione peroxidase 4 (GPX4). Optimal CD8+ T cell-mediated anti-tumor immunity depends on acyl-CoA synthetase long chain family member 4 (ACSL4), which promotes ferroptosis sensitivity. Moreover, we determined that overexpression of GPX4 or ferroptosis suppressor protein 1 (FSP1) generates ferroptosis-resistant CD8+ T cells, which may be valuable when systemic ferroptosis-inducing cancer therapies become available. To study how systemic metabolism impacts anti-tumor immunity, we modeled human obesity by feeding mice a high-fat diet (HFD). We demonstrated that HFD impairs CD8+ T cell function in the tumor microenvironment (TME) and accelerates tumor growth. MC38 tumor cells and CD8+ T cells display distinct metabolic adaptations with diet-induced obesity. The cancer cells increase fat uptake, resulting in depletion of fatty acids and fewer CD8+ T cells in HFD tumors. Accordingly, disabling cancer cell-intrinsic metabolic reprogramming with HFD improves anti-tumor immunity. Bioinformatic analyses revealed that similar metabolic rewiring correlates with reduced CD8+ T cell infiltration in human cancers. A further characterization of CD8+ T cells with HFD demonstrated more frequent antigen-experienced phenotypes systemically but reduced activation in the TME. This dysfunction depends on the HFD environment and can be rescued by anti-PD-1 therapy. Together, our studies have highlighted how anti-tumor immunity is impacted by T cell-intrinsic and systemic metabolism. Specifically, our results suggest that the handling of fats, both intracellularly, in the TME, and systemically, is a critical regulator of the anti-tumor CD8+ T cell response.