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Epigenetic control of CD8+ T cell responsiveness to a-PD-1 by Suv39h1: Contrôle épigénétique de la réactivité des cellules T CD8+ à l'a-PD-1 par Suv39h1

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 that genetic ablation or pharmacological inhibition of H3K9-methyl transferase 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 IFN-γ and GZMb-producing effector cells that express negative checkpoints, 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.
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Preprints, Working Papers, ...
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https://hal.archives-ouvertes.fr/hal-03041343
Contributor : Geneviève Almouzni Connect in order to contact the contributor
Submitted on : Friday, December 4, 2020 - 8:07:53 PM
Last modification on : Tuesday, October 19, 2021 - 11:39:54 AM

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Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, et al.. Epigenetic control of CD8+ T cell responsiveness to a-PD-1 by Suv39h1: Contrôle épigénétique de la réactivité des cellules T CD8+ à l'a-PD-1 par Suv39h1. 2020. ⟨hal-03041343⟩

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