Graduate Student St. Jude Children’s Res. Hosp., University of Tennessee Health Science Center, United States
Introduction/Rationale: The effectiveness of T cell-based immunotherapy is limited due to T cell exhaustion, a state of impaired cytotoxicity, diminished cytokine production, and restricted proliferative capacity during chronic antigen exposure. Epigenetic modifications, such as the acquisition of repressive DNA methylation, sustain T cell exhaustion. Here, we investigate the role of hypomethylating agents in reversing T cell dysfunction via DNA demethylation. We hypothesize that using a selective inhibitor of DNA methyltransferase 1 (DNMT1i), GSK-3685032, can overcome the fate restrictions unique to terminally differentiated T-cells. Our preliminary data show that the fate and subset specificity of human and mouse T-cells can be epigenetically altered to mediate the reversal of repressive epigenetic programs.
Methods: Methylation profiling revealed that DNMT1i treatment results in robust loss of DNA methylation, notably at critical memory and stem-associated gene loci including TCF7 and LEF1.
Results: Notably, DNMT1i-treated T cells that underwent division had decreased methylation coupled to heightened multipotency and plasticity. Single-cell transcriptomics post DNMT1i treatment reinforced our findings by revealing a unique subset of memory T cells that have homing potential and a long-lived memory gene signature.
Conclusion: Collectively, we describe an epigenetic approach that facilitates the reversal of repressive DNA methylation and are now using this approach to alter the fate of T cell subsets for immunotherapy.
