Dataset Information

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⁺ T-cell proliferation, IFN? production, and tumor cell cytotoxicity. Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the ?-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.

SUBMITTER: Zhou L

PROVIDER: S-EPMC6942613 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Zhou Liye L Mudianto Tenny T Ma Xiaojing X Riley Rachel R Uppaluri Ravindra R

Clinical cancer research : an official journal of the American Association for Cancer Research 20190927 1

<h4>Purpose</h4>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.<h4>Experimental design</h4>EZH2 regulation of antigen presentation was defined using EZH2 inhibitors (GSK126 and EPZ64 ...[more]

PMID: 31562203

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Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

Similar Datasets

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