Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy.
Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy.
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DOI：
10.1158/2326-6066.cir-20-0372
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发表时间：
2020-10
影响因子：
10.1
通讯作者：
Dougan M
中科院分区：
文献类型：
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作者：
Dougan M
检查点阻断免疫疗法在各种肿瘤中产生了令人印象深刻的治疗反应，但也导致了一系列炎症毒性，这些毒性可能涉及体内的任何器官系统。虽然大多数炎症毒性通过全身免疫抑制而消退，但可能发生致命的毒性，并且由于毒性而中断和停止免疫治疗是常见的。除了它们的临床影响外，这些炎症毒性还为人类的免疫调节提供了一个窗口。通过研究驱动这种炎症的细胞和分子机制，我们有机会了解免疫检查点，细胞毒性T淋巴细胞抗原（CTLA）-4，程序性死亡（PD）-1及其配体（PD-L1）如何维持整个身体的免疫稳态。虽然我们对驱动有效抗肿瘤免疫的机制有了越来越详细的了解，但我们对毒性机制有了初步的了解。大多数毒性涉及屏障器官，表明与环境（包括微生物组）相互作用的重要作用。早期的分析涉及细胞毒性T细胞，尽管这些细胞识别的抗原以及它们及其周围激活的途径仍然未知。通过详细了解毒性的免疫机制，我们有可能为它们开发新的干预措施。这些治疗应该利用有效的抗肿瘤免疫和器官炎症的主要驱动因素之间的差异。通过靶向这些机制差异，我们可以开发出可与免疫疗法一起使用的疗法，阻断炎症毒性，同时保持甚至增强对癌症的反应。
Checkpoint blockade immunotherapy has led to impressive therapeutic responses in a wide variety of tumors, but also leads to a spectrum of inflammatory toxicities that can involve any organ system in the body. Although most inflammatory toxicities resolve with systemic immune suppression, fatal toxicities can occur, and interruption and discontinuation of immunotherapy because of toxicity is common. In addition to their clinical impact, these inflammatory toxicities also provide a window into immune regulation in humans. By studying the cellular and molecular mechanisms that drive this inflammation, we have an opportunity to learn how the immune checkpoints, cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1 and its ligand (PD-L1), maintain immune homeostasis throughout the body. Although we have an increasingly detailed understanding of the mechanisms that drive effective antitumor immunity, we have a rudimentary picture of the mechanisms of toxicity. Most toxicities involve barrier organs, suggesting an important role for interactions with the environment, including the microbiome. Early analyses have implicated cytotoxic T cells, though the antigens recognized by these cells, and the pathways activated by and around them are still unknown. By gaining a detailed understanding of the immune mechanisms of toxicity, we have the potential to develop novel interventions for them. These treatments should take advantage of differences between effective antitumor immunity and the principal drivers of organ inflammation. By targeting these mechanistic differences, we can develop therapies that can be used alongside immunotherapy, blocking inflammatory toxicity while preserving or even enhancing the response to cancer.