1. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas
- Author
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Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena, Eliane Piaggio, Institut Curie [Paris], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Inventiva [Daix], Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ALMOUZNI, Geneviève, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), and AMIGORENA, Sebastian
- Subjects
Multidisciplinary ,[SDV]Life Sciences [q-bio] ,Programmed Cell Death 1 Receptor ,General Physics and Astronomy ,General Chemistry ,Methyltransferases ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,Repressor Proteins ,[SDV] Life Sciences [q-bio] ,Lymphocytes, Tumor-Infiltrating ,Humans ,Melanoma - Abstract
Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.
- Published
- 2022