Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Mol Cancer. 2021 Dec 20;20(1):171. doi: 10.1186/s12943-021-01464-x.
Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.
表观遗传机制不仅在癌症的发生和进展中起着至关重要的作用，而且在免疫细胞的激活、分化和效应功能方面也起着至关重要的作用。在这篇综述中，我们总结了与影响免疫细胞命运和功能以及癌细胞免疫原性的免疫细胞中表观基因组动态相关的当前文献。一些重要的免疫相关基因，如颗粒酶 B、IFN-γ、IL-2、IL-12、FoxP3 和 STING，在免疫细胞和癌细胞中通过表观遗传机制进行调节，免疫细胞和肿瘤相关基质细胞表达的免疫检查点分子（PD-1、CTLA-4、TIM-3、LAG-3、TIGIT）也是如此。因此，实施表观遗传调节药物的治疗策略有望通过促进局部免疫细胞群体的转录和代谢重编程，显著影响肿瘤微环境（TME），从而抑制抑制性细胞（MDSCs 和 Treg）并激活抗肿瘤 T 效应细胞、专业抗原提呈细胞（APC），以及可以作为非专业 APC 的癌细胞。在后一种情况下，表观遗传调节剂可能通过诱导转录抑制的肿瘤相关抗原的新表达、增加新抗原的表达和 MHC 加工/呈递机制，以及激活肿瘤免疫原性细胞死亡（ICD），协同促进肿瘤免疫原性。ICD 为抗肿瘤 T 细胞交叉呈递提供了丰富的免疫原来源，并使癌细胞对介入性免疫治疗敏感。通过这种方式，表观遗传调节剂可以被设想为能够介导卓越治疗效果的联合免疫治疗方法的有效成分。
