Tu158 - Antigen-driven Epigenetic Rewiring Drives Rapid Exhaustion of Memory T Cells in Progressing Tumors

Ardiana Moustaki, PhD – St Jude Children's Research Hospital; Benjamin Youngblood, PhD – Immunology – St. Jude Children's Research Hospital; Andrea Schietinger, PhD – Immunology – Memorial Sloan Kettering Cancer Center

Abstract Text: When naive antigen-specific CD8 T cells encounter antigens in an acute inflammatory context (e.g. acute infection), T cells undergo clonal expansion and differentiate into cytolytic effector T cells. After pathogen or antigen clearance, most effector T cells die, but a small fraction survive and form long-lasting memory T cells. There are three functional hallmarks that distinguish memory T cells from their naïve counterparts: they are long-lived, able to self-renew, and have a lower activation threshold. We and others have shown that the memory T cell state is encoded epigenetically, through gene poising and transcriptional memory. Due to this epigenetically-imprinted superior functionality it is thought that memory T cells would retain their qualitative and quantitative superiority also in settings of persistent antigen encounter, such as in tumors. In fact, memory T cells are currently being selected as precursor T cells for the generation of gene-modified TCR- or CAR-transduced T cells for adoptive T cell therapy for the treatment of cancers. Here, we tested whether memory T cells could delay or resist differentiation to exhaustion and dysfunction during tumorigenesis. Surprisingly, we found that memory T cells became exhausted and lost effector function more rapidly and profoundly compared to their naïve counterparts, revealing unexpected limitations of memory T cells in settings of persistent tumor antigen. Here, we present novel insights in the epigenetic regulatory mechanisms, including genome-wide DNA-methylation modules, which drive rapid exhaustion of memory T cells in tumors with important implications for the development of cancer immunotherapeutic strategies.