Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology
Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Harvard Medical School
Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Massachusetts Institute of Technology and Harvard University - Broad Institute; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)
Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)
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.
Keywords: TCF1; neoantigen; immunodominance; CCR6; Tc17; vaccine; lung cancer
Burger, Megan and Cruz, Amanda M. and Crossland, Grace E. and Gaglia, Giorgio and Ritch, Cecily C. and Blatt, Sarah E. and Bhutkar, Arjun and Canner, David and Kienka, Tamina and Tavana, Sara and Garmilla, Andrea and Schenkel, Jason and Hillman, Michelle and de los Rios Kobara, Izumi and Li, Amy and Hwang, William and Westcott, Peter and Regev, Aviv and Santagata, Sandro and Jacks, Tyler E., Antigen Dominance Hierarchies Shape TCF1+ Progenitor CD8 T Cell Phenotypes in Tumors. Available at SSRN: https://ssrn.com/abstract=3770111 or http://dx.doi.org/10.2139/ssrn.3770111
This version of the paper has not been formally peer reviewed.
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