Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Durham, NC, United States.
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, United States.
Front Immunol. 2019 Dec 10;10:2876. doi: 10.3389/fimmu.2019.02876. eCollection 2019.
The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.
绝大多数与癌症相关的死亡是由于转移，这是一个需要逃避宿主免疫系统的过程。此外，由于原发性或继发性免疫治疗抵抗，相当一部分癌症患者不能从我们目前的免疫治疗武器库中获益。重要的是，已经证明某些树突状细胞 (DC) 亚群对于产生对检查点抑制剂免疫治疗的反应是不可或缺的。这些观察结果与 DC 在抗原交叉呈递和产生有效抗肿瘤免疫方面的关键作用一致。因此，预计开发有效的肿瘤外在机制来调节 DC 将是逃避免疫监视和各种免疫治疗策略的有效策略。尽管具有这种关键作用，但对于癌症如何破坏 DC 功能的方法知之甚少。在此，我们重点关注正在发展的癌症用来篡夺和耐受局部 DC 群体的那些选择机制。我们讨论了癌症在肿瘤微环境中诱导 DC 耐受的报道机制，描述了这些机制的演变与涉及肿瘤发生和转移的间充质转化过程之间的各种相似之处，并强调了逆转这些机制的策略，以提高目前可用的检查点抑制剂免疫疗法的疗效。
