Pillai, ShivDrijvers, Jefte Manuel2021-08-0420202020-09-282020-11Drijvers, Jefte Manuel. 2020. Metabolic regulation of anti-tumor CD8+ T cell responses. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.28149048https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37368943Cancer 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.application/pdfenCancer immunologyCD8+ T cellsDiet-induced obesityFerroptosisLipidsMetabolismImmunologyThesis or Dissertation2021-08-040000-0002-5675-5643