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Article Dans Une Revue Nature Communications Année : 2022

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

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

Résumé

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.

Dates et versions

hal-03810409 , version 1 (11-10-2022)

Identifiants

Citer

Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, et al.. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas. Nature Communications, 2022, 13 (1), pp.3739. ⟨10.1038/s41467-022-31504-z⟩. ⟨hal-03810409⟩
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