Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico Aviano, National Cancer Institute, Aviano, Italy.
Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
Pharmacol Ther. 2014 Jun;142(3):339-50. doi: 10.1016/j.pharmthera.2013.12.015. Epub 2013 Dec 30.
Continuously improving knowledge of the fine mechanisms regulating cross-talk between immune cells, and of their multi-faceted interactions with cancer cells, has prompted the development of several novel immunotherapeutic strategies for cancer treatment. Among these, modulation of the host's immune system by targeting immunological synapses has shown notable clinical efficacy in different tumor types. Despite this, objective clinical responses and, more importantly, long-term survival are achieved only by a fraction of patients; therefore, identification of the mechanism(s) responsible for the differential effectiveness of immune checkpoint blockade in specific patient populations is an area of intense investigation. Neoplastic cells can activate multiple mechanisms to escape from immune control; among these, epigenetic reprogramming is emerging as a key player. Selected tumor-associated antigens, Human Leukocyte Antigens, and accessory/co-stimulatory molecules required for efficient recognition of neoplastic cells by the immune system have been shown to be epigenetically silenced or down-regulated in cancer. Consistent with the inherent reversibility of epigenetic silencing, "epigenetic" drugs, such as inhibitors of DNA methyltransferases and of histone deacetylases, can restore the functional expression of these down-regulated molecules, thus improving the recognition of cancer cells by both the innate and adaptive immune responses. This review focuses on the immunomodulatory activity of epigenetic drugs and on their proposed clinical use in novel combined chemo-immunotherapeutic regimens for the treatment of solid tumors.
不断深入了解调节免疫细胞串扰的精细机制，以及它们与癌细胞的多方面相互作用，促使人们开发了几种新的癌症免疫治疗策略。其中，通过靶向免疫突触来调节宿主免疫系统，在不同的肿瘤类型中显示出显著的临床疗效。尽管如此，只有一部分患者能获得客观的临床反应，更重要的是，长期生存；因此，确定免疫检查点阻断在特定患者群体中具有不同疗效的机制是一个研究热点。肿瘤细胞可以激活多种机制来逃避免疫控制；其中，表观遗传重编程是一个关键因素。已经表明，肿瘤相关抗原、人类白细胞抗原和辅助/共刺激分子，这些是免疫系统有效识别肿瘤细胞所必需的，在癌症中被表观遗传沉默或下调。与表观遗传沉默的固有可逆性一致，“表观遗传”药物，如 DNA 甲基转移酶和组蛋白去乙酰化酶抑制剂，可以恢复这些下调分子的功能表达，从而改善先天和适应性免疫反应对癌细胞的识别。这篇综述重点介绍了表观遗传药物的免疫调节活性及其在新型联合化疗免疫治疗方案中的临床应用，以治疗实体瘤。
