660 Targeting T cell fates: converting exhaustion to memory to improve immunotherapeutic responses to cancer

Background In cancer, CD8+ T cells have the power to target and kill tumor with precision, but often fail due chronic activation from immunosuppressive microenvironment (TME). that experience prolonged in TME differentiate into a severely dysfunctional cell state known as exhaustion. healthy tissues, tissue-resident memory (TRM) response infection, which remain lodged tissues provide protection reinfection. When TRM-like are found patient tumors, they correlated improved outcomes responses immunotherapy. Understanding how manipulate fates an effort prevent exhaustion favor TRM-characteristics could benefit cancer Methods To explore differences between these states, we screened core TRM gene-expression signatures for genes downregulated undergo terminal Targets were then overexpressed antigen-specific adoptively transferred tumor-bearing mice analysis. Results Interestingly, many related protein regulation processing identified, including novel gene called Neuralized E3 Ubiquitin Protein Ligase 3 (Neurl3). Neurl3's function is not well described, however, experimentally mutating RING domain suggests Neurl3 transfers ubiquitin proteins degradation. was tumor-specific cells, infiltrating lymphocytes still upregulated inhibitory receptors PD1 Tim3, showed enhanced anti-tumor function. Neurl3-overexpressing had increased accumulation TME, canonical markers CD69 CD103, produced more cytokines, controlled growth, mouse survival B16 melanoma. Conclusions These results highlight understudied field of negative by degradation differentiation fate uncover potential immunocellular therapies functional cancer. Ethics Approval The study approved UCSD's Institutional Animal Care Use Committee, protocol number S04105.