Abstract IA12: Fueling T cells in inflammation and cancer

Abstract

Abstract Lymphocyte activation leads to rapid proliferation and differentiation, and we have shown that CD4 T-cell subsets are metabolically distinct. These specific metabolic programs may allow new understanding and approaches to manipulate immunity. Using metabolic network analysis of metabolomics and proteomics, we defined several metabolic nodes differentially utilized by CD4 T-cell subsets, including glutamine metabolism. By genetically deleting the glucose transporter Glut1 or the glutaminolysis enzyme, glutaminase (GLS), we have shown that glycolysis and glutaminolysis are both used by activated T cells. All effector T cells require Glut1 and glycolysis. In contrast, we found that Th17 cells preferentially require GLS while Th1 cells are actively impaired by this enzyme. Thus, inhibition of GLS both reduces Th17 responses and promotes differentiation of Th1 cells and can lead to signs of T-cell exhaustion. We show that GLS deficiency can protect against Th17-mediated inflammatory models and also can augment effector function of Th1 CAR-T cells against B-cell targets. Understanding mechanisms that regulate T-cell metabolism may provide new tools to modulate immunity in the balance of T-cell effector populations to both suppress inflammation and promote effector function. Citation Format: Jeffrey C. Rathmell. Fueling T cells in inflammation and cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA12.