New insights into epigenetic regulation of resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms and therapeutic opportunities

Experimental Hematology & Oncology

Review

Hua Yang¹  Miao Liu²  Hua You³  Mengyuan Dai³  Can Küçük⁴ 

[1] Department of Basic Medicine and Biomedical Engineering, School of Medical, Foshan University, Foshan, China;Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA;Laboratory for Excellence in Systems Biomedicine of Pediatric Oncology, Department of Hematology and Oncology, Pediatric Research Institute, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, International Science and Technology Cooperation base of Child development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, 136 Zhongshan Second Rd., Yuzhong District, 401122, Chongqing, China;İzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Türkiye;Basic and Translational Research Program, İzmir Biomedicine and Genome Center, İzmir, Türkiye;Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir, Türkiye;

关键词: PD-1/PD-L1;    Immune checkpoints;    Therapy resistance;    Epigenetic regulation;    DNA methyltransferase;    Histone deacetylase;    Non-coding RNA;   

DOI  :  10.1186/s40164-022-00356-0

 received in 2022-09-09, accepted in 2022-10-31,  发布年份 2022

来源: Springer

【 摘 要 】

Programmed cell death protein 1(PD-1) is a type of immune-inhibitory checkpoint protein, which delivers inhibitory signals to cytotoxic T cells by binding to the programmed death ligand-1 (PD-L1) displayed on the surface of cancer cells. Antibodies blocking PD-1/PD-L1 interaction have been extensively used in treatment of human malignancies and have achieved promising outcomes in recent years. However, gradual development of resistance to PD-1/PD-L1 blockade has decreased the effectiveness of this immunotherapy in cancer patients. The underlying epigenetic mechanisms need to be elucidated for application of novel strategies overcoming this immunotherapy resistance. Epigenetic aberrations contribute to cancerogenesis by promoting different hallmarks of cancer. Moreover, these alterations may lead to therapy resistance, thereby leading to poor prognosis. Recently, the epigenetic regulatory drugs have been shown to decrease the resistance to PD-1/PD-L1 inhibitors in certain cancer patients. Inhibitors of the non-coding RNAs, DNA methyltransferases, and histone deacetylases combined with PD-1/PD-L1 inhibitors have shown considerable therapeutic efficacy against carcinomas as well as blood cancers. Importantly, DNA methylation-mediated epigenetic silencing can inhibit antigen processing and presentation, which promotes cancerogenesis and aggravates resistance to PD-1/PD-L1 blockade immunotherapy. These observations altogether suggest that the combination of the epigenetic regulatory drugs with PD-1/PD-L1 inhibitors may present potential solution to the resistance caused by monotherapy with PD-1/PD-L1 inhibitors.

【 授权许可】

CC BY   
© The Author(s) 2022. corrected publication 2022

【 图 表 】

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