Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about their interplay and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we find that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens are enriched for a TCF1+ progenitor phenotype that has been correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response does not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ progenitor cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets indicates CCR6+ TCF1+ cells exist across human cancers and correlate with poor ICB response. Vaccination eliminates CCR6+ TCF1+ cells and dramatically expands the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.