EZH2 + PD-1 inhibitor to enhance the therapeutic effect of prostate cancer

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Nature Cancer: EZH2 + PD-1 inhibitor to enhance the therapeutic effect of prostate cancer

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EZH2 + PD-1 inhibitor to enhance the therapeutic effect of prostate cancer. Prostate cancer (PCa) is an important cause of cancer death.

Unfortunately, metastatic castration-resistant prostate cancer (mCRPC) is still incurable.

Although immune checkpoint therapy can produce a significant response in 15-20% of cancer patients, it is only effective in about 5% of PCa patients.

The resistance of prostate cancer patients to immune checkpoint therapy is believed to be related to low tumor immunogenicity and immunosuppressive tumor microenvironment.

EZH2 is a popular target in the field of epigenetic anti-tumor research in recent years. Increased expression and activity of EZH2 are important factors in the occurrence and development of prostate cancer.

Tumors with enhanced EZH2 function often exhibit immunosuppressive tumor microenvironment and immunotherapy resistance.

However, the epigenetic mechanism of EZH2-mediated prostate cancer resistance to immune checkpoint therapy has not been confirmed.

On March 22, 2021, researchers from the Dana-Farber Cancer Institute in the United States published a titled “EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in Nature Cancer Prostate cancer” research paper.

The study shows that inhibiting EZH2 can reduce the resistance of prostate cancer to immune checkpoint therapy.

It is suggested that the combination therapy of EZH2 inhibitor + immune checkpoint inhibitor can increase the immunotherapy effect of prostate cancer and can be used as a promising treatment plan.

In this study, the research team explored the effect of EZH2 loss of function on prostate cancer cell activation and PD-1 treatment resistance to determine the epigenetic mechanism of EZH2-mediated prostate cancer resistance to immune checkpoint therapy.

The research team first used genetically engineered prostate cancer mouse models (GEMM) expressing oncogenes cMYC, EZH2 alleles and inducible Cre recombinase (EMC mice) driven by the prostate-specific antigen (PSA) promoter Through RNA seq and ImageStream flow cytometry, it was found that EZH2 negatively regulates type I/II interferon-stimulating genes (ISG) in prostate cancer.

In order to further understand the potential mechanism of EZH2 inhibiting ISG, the research team used publicly published chromatin immunoprecipitation (ChIP) data sets of prostate cancer patients and cell lines and genetic mice and cell lines to prove the inner hospital retrovirus sequences (ERVs) Directly down-regulating the activation of ISGs after EZH2 inhibition and STING are essential for up-regulating the anti-cancer immunogenicity of EZH2 inhibition.

Next, the research team used the B6-HiMYC-PCa transgenic tissue transplantation mouse model and found that EZH2 inhibition or PD-1 treatment alone did not show anti-tumor activity, but the combination therapy produced significant therapeutic effects.

In vitro cytotoxicity tests proved EZH2 The inhibition of activity leads to a significant loss of immune-mediated cytotoxicity, which depends on the upregulation of tumor cell PD-L1.

In general, chemical or genetic inhibition of EZH2 in tumor cells will inhibit cell endogenous dsRNA, resulting in enhanced STING-ISG response, immune cell activation and sensitivity to PD-1 blockade.

These findings provide substantial insights for the immunotherapy of prostate cancer, and propose the possibility of EZH2 activity stratifying patients, and provide a theory for the development of EZH2 inhibitors as a therapeutic strategy to enhance the response of prostate cancer to immune checkpoint immunotherapy in accordance with.

Nature Cancer: EZH2 + PD-1 inhibitor to enhance the therapeutic effect of prostate cancer

(source:internet, reference only)

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