Dougan Michael
Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Cancer Immunol Res. 2020 Oct;8(10):1230-1235. doi: 10.1158/2326-6066.CIR-20-0372.
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 are 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-4 and programmed death-1 and its ligand, 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, although 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.
免疫检查点阻断免疫疗法已在多种肿瘤中产生了令人瞩目的治疗反应，但也会引发一系列炎症毒性反应，这些反应可能累及身体的任何器官系统。尽管大多数炎症毒性反应可通过全身免疫抑制得到缓解，但仍可能发生致命毒性反应，并且因毒性反应而中断和停止免疫治疗的情况很常见。除了其临床影响外，这些炎症毒性反应还为了解人类免疫调节提供了一个窗口。通过研究引发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4、程序性死亡蛋白1及其配体是如何在全身维持免疫稳态的。尽管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，但对毒性机制的认识仍很初步。大多数毒性反应涉及屏障器官，这表明与包括微生物群在内的环境相互作用具有重要作用。早期分析表明细胞毒性T细胞参与其中，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不清楚。通过深入了解毒性的免疫机制，我们有可能开发出针对它们的新型干预措施。这些治疗方法应利用有效抗肿瘤免疫与器官炎症主要驱动因素之间的差异。通过针对这些机制差异，我们可以开发出可与免疫疗法联合使用的疗法，在阻断炎症毒性的同时保留甚至增强对癌症的反应。
