Abstract

Abstract In order to drive a productive T-cell response to checkpoint immunotherapy, tumors must be sufficiently antigenic. However, antigens vary in their degree of immunogenicity and consequently drive T-cell responses of different magnitudes and quality. In a genetically engineered mouse model of lung adenocarcinoma expressing model T-cell antigens, we find that antigen dominance hierarchies are established in tumors, where the T-cell response is largely focused on a dominant epitope as observed in viral infections. Interestingly, while T cells responding to a subdominant antigen are fewer in number, we find that they are less exhausted and express more markers of memory cells. T cells responding to the dominant antigen rapidly contract, while those responding to the subdominant antigen persist better over time. Despite their seemingly greater functional potential, T cells responding to the subdominant antigen fail to respond significantly to checkpoint immunotherapy in the context of this dominance hierarchy. Remarkably, removal of the dominant antigen unleashes the subdominant response and these cells expand to fill the effector niche previously occupied by the dominant response. Current experiments are testing the ability of vaccination to “break dominance” and improve the contribution of the subdominant response to tumor control. These findings could have great relevance to the design of personalized cancer vaccines, where targeting subdominant antigens over dominant antigens may lead to surprising therapeutic benefit. This abstract is also being presented as Poster B36. Citation Format: Megan L. Burger, Grace E. Crossland, Jason M. Schenkel, David A. Canner, Tyler Jacks. Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR11.

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