Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation.
Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation.
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DOI：
10.3389/fcell.2021.664305
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Li CM;Chen Z
最近的流行病学研究发现，50岁以下成年人的癌症发病率呈惊人的上升趋势，并预测今后10年这一年龄组的癌症发病率将大幅上升。这一趋势体现在非贲门胃癌的发病率及其对50岁以下非西班牙裔白色女性的不成比例的影响。这一趋势与工业化国家自身免疫性疾病发病率的增加同时出现，表明两者之间存在因果关系。虽然自身免疫被怀疑是某些癌症的危险因素，但自身免疫与癌症之间联系的确切机制仍不清楚，而且经常存在争议。这种联系被归因于几种介质，如免疫抑制，感染，饮食，环境，或者可能最明显的是，慢性炎症，因为它在肿瘤发生中的作用是公认的。在这方面，自身免疫性疾病是慢性炎症的常见原因，并可能引发抗原特异性细胞损伤、组织再生和伤口愈合的重复循环。说明自身免疫性疾病与癌症之间的联系的是具有与细胞毒性T淋巴细胞相关蛋白4（CTLA 4）的遗传易感性不足相关的癌症发展风险增加的患者，细胞毒性T淋巴细胞相关蛋白4是针对自身免疫的原型免疫检查点，并且是癌症免疫治疗的主要靶标之一。由CTLA 4不足触发的肿瘤发生过程已在小鼠模型中显示依赖于2型细胞因子白细胞介素-4（IL 4）和白细胞介素-13（IL 13）。在这种2型炎性环境中，与2型免疫细胞的串扰可能启动上皮细胞的表观遗传重编程，导致化生分化，并最终恶性转化，即使在不存在经典致癌突变的情况下。这些发现补充了大量关于炎性肿瘤发生中1型、3型或其他炎性介质的证据。本文综述了自身免疫作为肿瘤发生的一个致病因素的潜力，潜在的炎症机制可能会因宿主环境的变化而异，以及对癌症预防和免疫治疗的影响。
Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.
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