Journal Article

CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas

Cohen, José L., Goudot, Christel, Waterfall, Joshua J., Almouzni, Geneviève, Luccarini, Jean-Michel, Quivy, Jean-Pierre, Soudé, Anne, Piaggio, Eliane, Ye, Mengliang, Caudana, Pamela, Zueva, Elina, Sedlik, Christine, Rodriguez, Raphaël, Ramos, Rodrigo Nalio, Colombeau, Ludovic, Bournique, Bruno, Thiolat, Allan, Denizeau, Jordan, Pace, Luigia, Baulande, Sylvain, Amigorena, Sebastian, Gueguen, Paul, Broqua, Pierre, Niborski, Leticia Laura

2022

Overview

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. Understanding CD8 + T cell response to immune checkpoint blockade at the molecular level is important for the design of more efficient cancer immune therapies. Authors show here that the histone lysine methyltransferase Suv39h1 controls the transcriptional programs that determine the functionality of CD8 + T cells and Suv39h1 inhibition may potentiate anti-PD-1 therapy of melanomas.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 45/91 / 49/23 / 631/250/2152/1566/1618 / 631/250/251 / 631/337/100/2285 / 631/67/1059/2325 / 64/60 / Ablation / Biomarkers / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell activation / Chromatin / Effector cells / Epigenesis, Genetic / Epigenetics / Granzyme B / Histone methyltransferase / Histones / Humanities and Social Sciences / Humans / Immune checkpoint / Immunological memory / Life Sciences / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Lysine / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - therapy / Methyltransferase / Methyltransferases - antagonists & inhibitors / Methyltransferases - genetics / Methyltransferases - immunology / Methyltransferases - metabolism / multidisciplinary / PD-1 protein / Physics / Pluripotency / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Programmed Cell Death 1 Receptor - metabolism / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Tumor-infiltrating lymphocytes / Tumors / γ-Interferon