1. Antigen dominance hierarchies shape TCF1 + progenitor CD8 T cell phenotypes in tumors.
- Author
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Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, Bhutkar A, Canner D, Kienka T, Tavana SZ, Barandiaran AL, Garmilla A, Schenkel JM, Hillman M, de Los Rios Kobara I, Li A, Jaeger AM, Hwang WL, Westcott PMK, Manos MP, Holovatska MM, Hodi FS, Regev A, Santagata S, and Jacks T
- Subjects
- Amino Acid Sequence, Animals, CTLA-4 Antigen metabolism, Epitopes, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms pathology, Mice, Peptides chemistry, Phenotype, Programmed Cell Death 1 Receptor metabolism, RNA-Seq, Receptors, Antigen, T-Cell metabolism, Receptors, CCR6 metabolism, Single-Cell Analysis, Vaccination, Adenocarcinoma of Lung immunology, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Hepatocyte Nuclear Factor 1-alpha metabolism, Lung Neoplasms immunology, Stem Cells immunology
- Abstract
CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found 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 were enriched for a TCF1
+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors., Competing Interests: Declaration of interests T.J. is on the board of directors of Amgen and ThermoFisher Scientific, a co-founder of Dragonfly Therapeutics and T2 Biosystems, an SAB member of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics and is president of Break Through Cancer. The T.J. lab receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support this research. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and ThermoFisher Scientific. A.R. is an employee of Genentech (Roche Group) from August 1, 2020. S.S. is a consultant for RareCyte, Inc. A.M.C. interned at Skyhawk Therapeutics. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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