研究人员表示，免疫检查点抑制剂可以刺激抗肿瘤免疫，但也可能诱发毒性反应，即免疫相关不良事件（irAE）。结肠炎是一种常见的严重irAE，可导致治疗中断。由于在接受检查点抑制剂治疗的实验室小鼠中观察不到结肠炎，因此对肠道irAE的机制理解一直受到阻碍。
研究人员发现，通过使用携带野生小鼠微生物群的小鼠可以克服这一局限性，野生小鼠在接受抗CTLA-4抗体治疗后会出现明显的结肠炎。肠道炎症是由产生IFNγ的CD4+ T细胞不受限制的活化和通过Fcγ受体信号消耗外周诱导的调节性T细胞驱动的。因此，缺乏Fc结构域的抗CTLA-4纳米抗体可以促进抗肿瘤反应，而不会引发结肠炎。这项研究提出了一种既能减轻肠道irAE，又能保持CTLA-4阻断的抗肿瘤刺激效应的策略。
附：英文原文
Title: Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors
Author: Bernard C. Lo, Ilona Kryczek, Jiali Yu, Linda Vatan, Roberta Caruso, Masanori Matsumoto, Yosuke Sato, Michael H. Shaw, Naohiro Inohara, Yuying Xie, Yu Leo Lei, Weiping Zou, Gabriel Núez
Issue&Volume: 2024-01-05
Abstract: Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.
DOI: adh8342
Source: https://www.science.org/doi/10.1126/science.adh8342