Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.
Keywords: 5-AzaC, 5-azacitidine; ACE1, angiotensin converting enzyme; ACP1, human red cell acid phosphatase; APC, antigen-presenting cell; BETi, bromodomain and extra-terminal motif inhibitors; CCL22 (MDC), macrophage-derived chemokine; CLL, chronic lymphocytic leukemia; CTA, cancer testis antigen; CTLA-4, cytotoxic T lymphocyte antigen 4; CTLs, cytotoxic T lymphocytes; CX3CL1, C-X3-C motif chemokine ligand 1; CXCL, CXC chemokine ligand; Cancer; DC, dendritic cell; DNMT1, DNA methyltransferase 1; DNMTi, DNA methyltransferase inhibitors; EZH2, enhancer of zeste homolog 2; Epigenetic regulation; FDA, U. S. Food and Drug Administration; FOXP3, forkhead box P3; H3K27me3, tri-methylation of lysine 27 on histone H3; HDACi, histone deacetylase inhibitor; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-gamma; Immune cycle; Immunotherapy; LAG-3, lymphocyte activation gene-3; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex; OS, overall survival; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; PD-L1/PD-1 blockade; PRC2, polycomb repressive complex 2; TAA, tumor-associated antigen; TET2, ten-eleven translocation 2; TH-1, T helper type 1; TIL, tumor infiltrating lymphocytes; TIM-3, T cell immunoglobulin and mucin domain 3; Tregs, regulatory T cells; UHRF1, ubiquitin-like PHD and RING finger domain-containing 1.
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