PKM2 regulates mitochondria dependent anti-tumor functions in CD8 T cells by modulating cell transcriptome, metabolome and methylome

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B614
Abstract ID: 4742

Presenting Author:
Vivek Verma , Assistant Professor at Hormel Institute, University of Minnesota

Abstract:

Loss of mitochondrial structure and function is associated with exhaustion and therapeutic failure of lymphocytes. Using the pharmacological agent TEPP46, we explored the mitochondrial and immune-modulatory effects of PKM2 in CD8 T cells. PKM2 differentially regulates the transcriptome, epigenome, metabolome, and effector functions in CD8 T cells. TEPP46 treatment differentially regulated the transcriptome, resulting in enhanced TCR-mediated effector functions along with PGC1a-directed mitochondrial biogenesis, OXPHOS, and gene expression supporting mitochondrial fusion and the MICOS complex. Whole-genome bisulfite sequencing showed hypomethylation of mtDNA and increased mitochondrial translation, enhancing mitochondrial mass and cristae density in TEPP46-treated lymphocytes. Metabolome analysis revealed differential regulation of the glycolytic and pentose phosphate pathways. Antigenic re-challenge of TEPP46-treated CD8 T cells showed stronger recall responses with sustained mitochondrial metabolism. TEPP46 treatment of B16 tumors in mice showed CD8 T cell-dependent anti-tumor responses and an increased infiltration, activation, and metabolic fitness of CD8 T cells with fewer Treg and MDSCs in tumors. In conclusion, we establish the unexplored roles of PKM2 in CD8 T cells, showing that PKM2 enhances effector functions and mitochondrial metabolism in cytotoxic cells, with potential applications in adoptive cell therapies and in-situ enhancement of CD8 T cell functions.