CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2022

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

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Paul Gueguen
Pamela Caudana
Anne Soudé
  • Function : Author
Bruno Bournique
  • Function : Author
Pierre Broqua
  • Function : Author
José Cohen

Abstract

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 and versions

hal-03877477 , version 1 (29-11-2022)

Identifiers

Cite

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-03877477⟩
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