Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Immunol. 2019 May 10;10:954. doi: 10.3389/fimmu.2019.00954. eCollection 2019.
Lung cancer is the leading cause of cancer death in men and women. Lung adenocarcinoma (LUAD), represents approximately 40% of all lung cancer cases. Advances in recent years, such as the identification of oncogenes and the use of immunotherapies, have changed the treatment of LUAD. Yet survival rates still remain low. Additionally, there is still a gap in understanding the molecular and cellular interactions between cancer cells and the immune tumor microenvironment (TME). Defining how cancer cells with distinct oncogenic drivers interact with the TME and new strategies for enhancing anti-tumor immunity are greatly needed. The complement cascade, a central part of the innate immune system, plays an important role in regulation of adaptive immunity. Initially it was proposed that complement activation on the surface of cancer cells would inhibit cancer progression via membrane attack complex (MAC)-dependent killing. However, data from several groups have shown that complement activation promotes cancer progression, probably through the actions of anaphylatoxins (C3a and C5a) on the TME and engagement of immunoevasive pathways. While originally shown to be produced in the liver, recent studies show localized complement production in numerous cell types including immune cells and tumor cells. These results suggest that complement inhibitory drugs may represent a powerful new approach for treatment of NSCLC, and numerous new anti-complement drugs are in clinical development. However, the mechanisms by which complement is activated and affects tumor progression are not well understood. Furthermore, the role of local complement production vs. systemic activation has not been carefully examined. This review will focus on our current understanding of complement action in LUAD, and describe gaps in our knowledge critical for advancing complement therapy into the clinic.
肺癌是男性和女性癌症死亡的主要原因。肺腺癌 (LUAD) 约占所有肺癌病例的 40%。近年来的进展，如癌基因的鉴定和免疫疗法的应用，改变了 LUAD 的治疗方法。然而，生存率仍然很低。此外，人们仍然对癌细胞与免疫肿瘤微环境 (TME) 之间的分子和细胞相互作用理解存在差距。定义具有不同致癌驱动因素的癌细胞如何与 TME 相互作用，以及增强抗肿瘤免疫的新策略，这是非常需要的。补体级联反应是先天免疫系统的核心部分，在调节适应性免疫中起着重要作用。最初提出，癌细胞表面的补体激活会通过膜攻击复合物 (MAC) 依赖性杀伤来抑制癌症进展。然而，来自几个小组的数据表明，补体激活通过 TME 上过敏毒素 (C3a 和 C5a) 的作用以及免疫逃避途径的参与促进癌症进展。虽然最初显示在肝脏中产生，但最近的研究表明，许多细胞类型包括免疫细胞和肿瘤细胞都有局部补体产生。这些结果表明，补体抑制药物可能代表治疗 NSCLC 的一种强大的新方法，并且许多新的抗补体药物正在临床开发中。然而，补体激活的机制及其对肿瘤进展的影响尚不清楚。此外，局部补体产生与系统激活的作用尚未仔细研究。这篇综述将重点介绍我们目前对 LUAD 中补体作用的理解，并描述推进补体治疗进入临床的关键知识差距。
