Elucidating the role of CD8α:MyD88 on CD8 T cell fate during response to solid tumors 2797

Abstract Description T cell exhaustion limits the efficacy of cancer immunotherapies. We have generated a CD8α:MyD88 construct that promotes robust T cell expansion and antitumor activity. As exhausted T cells are largely dysfunctional, we sought to investigate the influence of CD8α:MyD88 on T cell exhaustion. Our results indicate that CD8α:MyD88 TIL (1) downregulate inhibitory receptor gene and protein expression, (2) remain functional following ex vivo restimulation, and (3) maintain elevated expression of TCF1, suggesting that CD8α:MyD88 may oppose T cell exhaustion programing while promoting stemness. We hypothesize that expression of CD8α:MyD88 in T cells induces a unique transcriptional network that restrains terminal differentiation and concurrently supports a functional stem-like state, leading to sustained antitumor activity and development of immune memory. Our scRNAseq indicates that CD8α:MyD88 TIL exhibit a stem-like transcriptional signature rather than terminally differentiated/exhausted. Additionally, a consequence of T cell exhaustion is the failure to differentiate persisting memory T cells, limiting therapeutic durability. As TCF1 is a driver of memory differentiation and CD8α:MyD88 T cells express high TCF1, we employed a tumor control model to assess memory potential where CD8α:MyD88 T cells persisted and expanded upon rechallenge. Together, our results highlight new impacts of MyD88 on T cell differentiation in cancer which could be leveraged to augment T cell therapies. Funding Sources Supported by the CU Cancer Innovation Pilot Grant #P30CA046934, BX004935-01 Dept. of VA Merit Award, and R01CA271537 National Cancer Institute (NCI/NIH) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)