Abstract P010: Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet it is unclear whether they interact to potentiate or antagonize the overall anti-tumor response. In a genetically engineered mouse model of lung adenocarcinoma, we find that antigen dominance hierarchies are established in tumors wherein the antigen that most stably binds MHC dominates the CD8 T cell response. This negatively impacts the response to subdominant antigens, suppressing T cell expansion, differentiation and effector function; a phenotype that is reversed when the dominant antigen is removed. Intriguingly, the subdominant response is also enriched for a TCF1+ progenitor cell phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, we find that the subdominant response does not preferentially benefit from ICB due to predominance of a dysfunctional subset of TCF1+ cells marked by CCR6 expression and differentiation to a Tc17 phenotype. CCR6+ TCF1+ cells are also found broadly across human cancers and do not correlate with patient response to ICB. This subset appears to be derived from poor T cell receptor stimulation, due to competition of T cells for good interactions with antigen presenting cells. Vaccination eliminates CCR6+ TCF1+ cells and disrupts the antigen dominance hierarchy, preferentially expanding the subdominant CD8 T cell response in tumors. Overall enrichment of TCF1+ cells is maintained amongst the subdominant response post-vaccination and current studies are exploring whether this promotes more durable tumor control or better response to ICB. These findings provide strong rationale for evaluating the relative response to high versus low pMHC stability antigens in clinical trials of pooled neoantigen vaccines, where low stability, subdominant antigens may contribute more to tumor control than previously realized. Citation Format: Megan L. Burger, Amanda M. Cruz, Grace E. Crossland, Giorgio Gaglia, Cecily C. Ritch, Sarah E. Blatt, Arjun Bhutkar, Sara Z. Tavana, Sandro Santagata, Tyler Jacks. Antigen dominance hierarchies shape CD8 T cell phenotypes and immunotherapy response in tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P010.