Toomer Kevin H, Chen Zhibin
Department of Microbiology and Immunology, University of Miami Miller School of Medicine , Miami, FL , USA.
Department of Microbiology and Immunology, University of Miami Miller School of Medicine , Miami, FL , USA ; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine , Miami, FL , USA.
Front Immunol. 2014 Mar 18;5:116. doi: 10.3389/fimmu.2014.00116. eCollection 2014.
Cancer immunotherapy through manipulation of the immune system holds great potential for the treatment of human cancers. However, recent trials targeting the negative immune regulators cytotoxic T-lymphocyte antigen 4, programed death 1 (PD-1), and PD-1 receptor ligand (PD-L1) demonstrated that clinically significant antitumor responses were often associated with the induction of autoimmune toxicity. This finding suggests that the same immune mechanisms that elicit autoimmunity may also contribute to the destruction of tumors. Given the fact that the immunological identity of tumors might be largely an immunoprivileged self, autoimmunity may not represent a wholly undesirable outcome in the context of cancer immunotherapy. Rather, targeted killing of cancer cells and autoimmune damage to healthy tissues may be intricately linked through molecular mechanisms, in particular inflammatory cytokine signaling. On the other hand, since chronic inflammation is a well-recognized condition that promotes tumor development, it appears that autoimmunity can be a "double agent" in mediating either pro-tumor or antitumor effects. This review surveys the tumor-promoting and tumoricidal activities of several prominent cytokines: IFN-γ, TNF-α, TGF-β, IL-17, IL-23, IL-4, and IL-13, produced by three major subsets of T helper cells that interact with innate immune cells. Many of these cytokines exert divergent and seemingly contradictory effects on cancer development in different human and animal models, suggesting a high degree of context dependence in their functions. We hypothesize that these inflammatory cytokines could mediate a feedback loop of autoimmunity, antitumor immunity, and tumorigenesis. Understanding the diverse and paradoxical roles of cytokines from autoimmune responses in the setting of cancer will advance the long-term goal of improving cancer immunotherapy, while minimizing the hazards of immune-mediated tissue damage and the possibility of de novo tumorigenesis, through proper monitoring and preventive measures.
通过操纵免疫系统进行癌症免疫治疗在人类癌症治疗中具有巨大潜力。然而，最近针对负性免疫调节因子细胞毒性T淋巴细胞相关抗原4、程序性死亡蛋白1（PD-1）及其受体配体（PD-L1）的试验表明，临床上显著的抗肿瘤反应往往与自身免疫毒性的诱导有关。这一发现表明，引发自身免疫的相同免疫机制可能也有助于肿瘤的破坏。鉴于肿瘤的免疫特性在很大程度上可能是一种免疫特权的自身，在癌症免疫治疗的背景下，自身免疫可能并非完全是不良结果。相反，癌细胞的靶向杀伤与健康组织的自身免疫损伤可能通过分子机制，特别是炎性细胞因子信号传导，错综复杂地联系在一起。另一方面，由于慢性炎症是一种公认的促进肿瘤发展的状况，自身免疫似乎可能是一种在介导促肿瘤或抗肿瘤效应方面的“双面剂”。本综述调查了由与固有免疫细胞相互作用的三类主要辅助性T细胞亚群产生的几种重要细胞因子：干扰素-γ、肿瘤坏死因子-α、转化生长因子-β、白细胞介素-17、白细胞介素-23、白细胞介素-4和白细胞介素-13的促肿瘤和杀肿瘤活性。在不同的人类和动物模型中，这些细胞因子中的许多对癌症发展具有不同且看似矛盾的作用，表明它们的功能高度依赖于环境。我们推测这些炎性细胞因子可能介导自身免疫、抗肿瘤免疫和肿瘤发生的反馈回路。了解癌症背景下自身免疫反应中细胞因子的多样和矛盾作用，将推动改善癌症免疫治疗这一长期目标的实现，同时通过适当的监测和预防措施，将免疫介导的组织损伤风险和新发肿瘤发生的可能性降至最低。
