Niborski et al. examined the effects of Suv39h1 (involved in heterochromatin organization and differentiation of Th1, Th2, and CTL) on responses to anti-PD-1 treatment. In Suv39h1-deficient mice, the delay of B16F10-OVA growth was modest and comparable to the delay in WT mice treated with anti-PD-1. The combination of Suv39h1 deficiency and anti-PD-1 in this and other models resulted in synergistic antitumor effects. Functional, scRNAseq, and chromatin accessibility analyses of CD8+ TILs indicated that Suv39h1 deficiency enhanced anti-PD-1-induced opening of TCR, cytolytic, and IFNα responsive sites and drove a transcriptomic phenotype found in responding patients with melanoma.
Contributed by Margot O’Toole
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.
Author Info: (1) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France.
Author Info: (1) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. (2) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. (3) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. (4) Universit Paris-Est, UMR S955, Universit Paris-Est Crteil Val de Marne, Crteil, France. INSERM, U955, Equipe 21, Crteil, France. (5) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. (6) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. (7) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. (8) Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, Chemical Biology of Cancer, Equipe Labellise Ligue contre le Cancer, Paris, France. (9) Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, Chemical Biology of Cancer, Equipe Labellise Ligue contre le Cancer, Paris, France. (10) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. (11) Inventiva, 50 rue de Dijon, 21121, Daix, France. (12) Inventiva, 50 rue de Dijon, 21121, Daix, France. (13) Inventiva, 50 rue de Dijon, 21121, Daix, France. (14) Inventiva, 50 rue de Dijon, 21121, Daix, France. (15) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. (16) Institut Curie, Genomics of Excellence (ICGex) Platform, Institut Curie Research Center, Paris, France. (17) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. (18) Institut Curie, PSL Research University, F-75005, Paris, France. Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellise Ligue contre le Cancer, Paris, France. Sorbonne Universits, UPMC University Paris 06, CNRS, UMR3664, F-7005, Paris, France. (19) Institut Curie, PSL Research University, F-75005, Paris, France. Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellise Ligue contre le Cancer, Paris, France. Sorbonne Universits, UPMC University Paris 06, CNRS, UMR3664, F-7005, Paris, France. (20) Universit Paris-Est, UMR S955, Universit Paris-Est Crteil Val de Marne, Crteil, France. INSERM, U955, Equipe 21, Crteil, France. (21) Institut Curie, PSL Research University, F-75005, Paris, France. INSERM U932, F-75005, Paris, France. (22) Institut Curie, PSL Research University, F-75005, Paris, France. Translational Research Department, Institut Curie, F-75005, Paris, France. INSERM U830, F-75005, Paris, France. (23) Institut Curie, PSL Research University, F-75005, Paris, France. sebastian.amigorena@curie.fr. INSERM U932, F-75005, Paris, France. sebastian.amigorena@curie.fr. (24) Institut Curie, PSL Research University, F-75005, Paris, France. eliane.piaggio@curie.fr. INSERM U932, F-75005, Paris, France. eliane.piaggio@curie.fr. Translational Research Department, Institut Curie, F-75005, Paris, France. eliane.piaggio@curie.fr.
