Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance

Abstract

BackgroundDespite the remarkable success of immunotherapy in treating melanoma, understanding of the underlying mechanisms of resistance remains limited. Emerging evidence suggests that upregulation of tumor-specific major histocompatibility complex-II (tsMHC-II) serves as a predictive marker for the response to anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) therapy in various cancer types. The genetic and epigenetic pathways modulating tsMHC-II expression remain incompletely characterized. Here, we provide evidence that polycomb repressive complex 2 (PRC2)/EZH2 signaling and resulting H3K27 hypermethylation suppresses tsMHC-II.MethodsRNA sequencing data from tumor biopsies from patients with cutaneous melanoma treated with or without anti-PD-1, targeted inhibition assays, and assays for transposase-accessible chromatin with sequencing were used to observe the relationship between EZH2 inhibition and interferon (IFN)-γ inducibility within the MHC-II pathway.ResultsWe find that increased EZH2 pathway messenger RNA (mRNA) expression correlates with reduced mRNA expression of both presentation and T-cell genes. Notably, targeted inhibition assays revealed that inhibition of EZH2 influences the expression dynamics and inducibility of the MHC-II pathway following IFN-γ stimulation. Additionally, our analysis of patients with metastatic melanoma revealed a significant inverse association between PRC2-related gene expression and response to anti-PD-1 therapy.ConclusionsCollectively, our findings demonstrate that EZH2 inhibition leads to enhanced MHC-II expression potentially resulting from improved chromatin accessibility atCIITA, the master regulator of MHC-II. These insights shed light on the molecular mechanisms involved in tsMHC-II suppression and highlight the potential of targeting EZH2 as a therapeutic strategy to improve immunotherapy efficacy.

Integrative analysis of single-cell and bulk RNA sequencing unveils a machine learning-based pan-cancer major histocompatibility complex-related signature for predicting immunotherapy efficacy

“…Since MHC-related genes were associated with drug resistance to tumor immunotherapy [ 17 , 18 ], we hypothesized that the level of MHC-related genes in patients could predict the efficacy of immunotherapy. We obtained MHCsig from 34 single-cell RNA sequencing datasets (Fig.…”

CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis

“…Top two pvalue ranked enriched transcription factors among the XLOC_030781 knock-downed genes included FOSL2 and NFE2L2 transcription factors and among the upregulated genes SUZ12 and EZH2, both components of the PRC2 repressor complex (Sauvageau & Sauvageau, 2010). Although all these transcription factors are already associated also as drivers of melanoma (Chen et al, 2021;James et al, 2023;Jessen et al, 2020;Terranova et al, 2021;Verma et al, 2022) their exact implications in XLOC_030781 phenotype drivers remain inconclusive.…”