Reversing defective priming in tumor-bearing hosts to rescue CD8 T cell function 2260686

Abstract

Abstract Introduction Tumor-specific CD8 T cells (TST) are often dysfunctional and fail to halt cancer progression. While chronic antigen stimulation is required to maintain the dysfunctional state , how T cell dysfunction initially arises in tumors was less clear. We recently demonstrated that TST lose effector function within hours of activation in tumor-bearing hosts; epigenetic and transcriptional analysis suggested that TST failed to activate inflammation-associated TF, resulting in loss of effector function. We therefore tested whether pathogen-associated molecular patterns (PAMP) signaling during initial priming could rescue T cell dysfunction in tumor-bearing hosts. Methods We used a preclinical liver cancer model in which tumors express the cognate antigen for transferred TCR-transgenic CD8 T cells (TCR-TAG), while antigen-free LM was used to provide PAMP signaling. Outcomes assessed were tumor outgrowth and T cell differentiation and function, determined by flow cytometry, RNA-SEQ, and ATAC-SEQ. Results TCR-TAG adoptively-transferred into mice with advanced liver tumors rapidly became dysfunctional: unable to produce effector cytokines (TNF alpha, IFN gamma) or cytotoxic molecules (granzyme B; GZMB). Remarkably, a single LM treatment rescued effector function; TCR-TAG expressed cytokines and GZMB, resulting in remarkable tumor reduction and prolonged survival. LM-induced PAMP signaling reprogrammed TST, suppressing stem/memory-associated transcription factors (TF), such as TCF1, and activating STAT-family TF. Importantly, LM treatment rescued TST function only when delivered within 24-48h after initial priming. Conclusion Our findings demonstrate that pathogen-driven inflammatory signaling during priming is required for TST cytotoxicity. However, LM/PAMP can cause toxicity, thus we are testing genome engineering strategies to activate PAMP-associated TF in TST, independent of LM/PAMP, to generate potent tumor-targeting T cells for adoptive immunotherapy. Funding Source 2T32CA009592 Microenvironment Influences in Cancer Training Program Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)