Jane Huang

"Role of transcription factor TOX in exhausted CD8 T cells maintenance"

Jane Yinghui Huang, Omar Khan, Josephine Giles, Amy Baxter, Jean-Christophe Beltra, E. John Wherry

Cellular immunotherapy and checkpoint blockade have emerged as promising therapeutic approaches against cancer; however, efficacy can be limited by T cell exhaustion. Substantial differences in chromatin accessibility and DNA methylation exist between exhausted T cells (TEX) and their more functional effector and memory counterparts. These chromatin changes correlate with limited responsiveness to checkpoint blockade and cytokine-mediated cellular reprogramming, necessitating improved understanding of the epigenetic determinants driving TEX fate commitment and maintenance. Our lab and others recently identified the HMG-box transcription factor TOX as an essential transcriptional and epigenetic initiator of TEX lineage differentiation. Here, I demonstrate that the maintenance of committed TEX remain dependent on continued TOX expression. Induced TOX ablation reduces TEX number, impairs expression of canonical TEX markers and impedes long-term TEX durability. This appears to be driven by impaired proliferation and survival of stem-cell-like TEX progenitors and, thus, their subsequent ability to repopulate the TEX pool. Furthermore, preliminary experiments suggest TOX enforces the TEX fate and represses the ability of TEX to be reprogrammed into effector and memory lineages. Subsequent experiments will determine whether TEX maintenance is undergirded by TOX-mediated enforcement of the TEX transcriptional and epigenetic program.