Targeting EZH2 Enhances Antigen Presentation, Antitumor Immunity, and Circumvents Anti–PD-1 Resistance in Head and Neck Cancer

Abstract

Purpose: Anti-programmed death-1 (PD-1) receptor-based therapeutics improve survival in patients with recurrent head and neck squamous cell carcinoma (HNSCC), but many do not benefit due to a low response rate. Herein, we identified EZH2 as a therapeutic target that enhanced tumor cell antigen presentation and subsequently sensitized resistant tumors to anti-PD-1 therapy.Experimental Design: EZH2 regulation of antigen presentation was defined using EZH2 inhibitors (GSK126 and EPZ6438) in human and mouse HNSCC cell lines. Mechanistic dissection of EZH2 in regulation of antigen presentation was investigated using flow cytometry, qRT-PCR, ELISA, and chromatin-immunoprecipitation assays. EZH2-deficient cell lines were generated using CRISPR-CAS9. GSK126 and anti-PD-1-blocking antibody were used in testing combinatorial therapy in vivo.Results: EZH2 expression was negatively correlated with antigen-processing machinery pathway components in HNSCC data sets in The Cancer Genome Atlas. EZH2 inhibition resulted in significant upregulation of MHC class I expression in human and mouse human papillomavirus-negative HNSCC lines in vitro and in mouse models in vivo. Enhanced antigen presentation on the tumor cells by EZH2 inhibitors or CRISPR-mediated EZH2 deficiency increased antigen-specific CD8 þ T-cell proliferation, IFNg production, and tumor cell cytotoxicity. Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the b-2-microglobulin promoter. Finally, in an anti-PD-1-resistant model of HNSCC, tumor growth was suppressed with combination therapy.Conclusions: Our results demonstrated that targeting EZH2 enhanced antigen presentation and was able to circumvent anti-PD-1 resistance. Thus, combining EZH2 targeting with anti-PD-1 may increase therapeutic susceptibility in HNSCC.

MiR-33a functions as a tumor suppressor in triple-negative breast cancer by targeting EZH2

“…Tazemetostat, an EZH2 inhibitor, has been approved for treating epithelioid sarcoma, and it is the first EZH2 inhibitor approved by FDA [47]. Other EZH2 inhibitor, GSK343 and GSK236, were also reported to inhibit tumor progression in various cancer, such as glioblastoma [48], head and neck cancer, [49] and breast cancer [50]. Our in vitro study confirmed the regulatory mechanism of miR-33a/EZH2 cascade in TNBC progression, thus, more investigation of the effects of miR-33a and EZH2 on tumor growth and metastasis in vivo is needed.…”

EZH2: a novel target for cancer treatment

“…In a phase 1/ 2, multi-center, open-label study (NCT03525795), the strategy of CPI-1205 plus ipilimumab is under evaluation in patients with advanced solid tumors. A recent study revealed the inhibition of EZH2 could enhance cancer cell antigen presentation in head and neck squamous cell carcinoma (HNSCC) and avoid anti-PD-1 resistance [95].…”

EZH2 as a Regulator of CD8+ T Cell Fate and Function

“…Thus, EZH2 is a relevant target in cancer therapies attempting to improve T cell recruitment into the TME. Specifically, expression of CXCR3 on T cells, which binds to ligands CXCL9/CXCL10, was highlighted in recent findings to be critical for drawing T cells into the TME and informs the design of future therapeutics with a primary aim of improving T cell recruitment (49,(52)(53)(54). Furthermore, the effect of EZH2 inhibition on destabilizing the regulatory T cell lineage is another primary consideration that was demonstrated to impact antitumor immunity (48,55).…”