Abstract PO-025: Mitochondrial elongation through Drp1 deletion increases CD8 T cell oxidative phosphorylation and memory formation

Abstract

Abstract Despite the positive effects of tumor infiltrating lymphocytes (TIL) seen in patients with melanoma and other tumor types, TIL often fail to completely control disease progression even with immune responses enhanced by checkpoint blockade or other immunotherapy. These TIL exhibit characteristics of exhaustion such as poor proliferation, poor effector function, and an increase in inhibitory receptor expression. By flow cytometry, we find that TIL have lower mitochondrial mass as well as lower mitochondrial membrane potential when compared to functional effector T-cells. During the activation and differentiation of T cells, the metabolic demands fluctuate between the necessity for glycolysis or oxidative phosphorylation (OXPHOS), which is supported by shifting of the mitochondrial network state. Using mice lacking Drp1, a mitochondrial fission protein, in T cells as a model of elongated mitochondria, we see increased spare respiratory capacity and OXPHOS as compared to WT T cells with fission capability. We find that these mice are more likely to generate memory precursor CD8 T cells as represented by KLRG1 lo and CD127 hi during a primary response to anti-CD40, PolyI:C, and ovalbumin protein. As indicated by the increase in memory precursors, we find that Drp1 −/− T cells form more memory than WT animals after a 28-day rest period. At this time, mice were challenged with an adenovirus expressing ovalbumin to elicit a recall response. This recall response of CD8 T cells is greater in animals lacking Drp1 in the T cells. In addition to the increase in T cell numbers, we anticipate an increase in the metabolic and possibly cytokine function of these cells, which is still under investigation. We aim to exploit mitochondrial dynamics to enforce elongation of the mitochondrial network of TIL in order to improve TIL functions and have begun investigations into mitochondrial elongation in T cells in mice bearing B16OVA melanoma tumors. Citation Format: Marissa A. Gonzales, Timothy NJ Bullock. Mitochondrial elongation through Drp1 deletion increases CD8 T cell oxidative phosphorylation and memory formation [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-025.