Immune checkpoint inhibitor (ICPI) can augment the anti-tumour response by blocking negative immunoregulators with monoclonal antibodies. The anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody is the first ICPI which has shown remarkable benefits in the clinical treatment of cancers. However, the increased activity of the immune system also causes some side effects called immune-related adverse events (irAEs). Colitis is one of the most common irAEs related to anti-CTLA-4 immunotherapy. We identified that CD4+ T cells were the primary responders in CTLA-4 blockade and that the expansion of gut-homing CD4+ T cells by anti-CTLA-4 therapy was independent of CD103. We used dextran sulfate sodium (DSS)-induced colitis mice as our model and tested the possibility of using a trafficking-blocking antibody to treat anti-CTLA-4 antibody-induced irAEs. We found that blocking T cell homing increased colitis severity in the context of CTLA-4 blockade and that gut-trafficking blockade had different effects on different Th subsets and could facilitate the proliferation of Th17 cells in the lamina propria (LP). Our data reveals the fundamental mechanism underlying trafficking-blocking antibody therapy for CTLA-4 blockade-induced colitis and provide a caution in regard to apply trafficking-blocking antibody treatment under CTLA-4 blockade condition.

中文翻译：

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T细胞运输在CTLA-4阻断诱导的肠道免疫病理学中的作用

免疫检查点抑制剂（ICPI）可通过用单克隆抗体阻断阴性免疫调节剂来增强抗肿瘤反应。抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）抗体是首个在临床治疗癌症中显示出显着优势的ICPI。但是，免疫系统活性的增强也会引起一些副作用，称为免疫相关不良事件（irAEs）。结肠炎是与抗CTLA-4免疫疗法有关的最常见的irAE之一。我们确定CD4 + T细胞是CTLA-4阻断的主要反应者，并且通过抗CTLA-4治疗使肠归巢的CD4 + T细胞的扩增独立于CD103。我们使用硫酸葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠作为我们的模型，并测试了使用转运阻断抗体治疗抗CTLA-4抗体诱导的irAE的可能性。我们发现，在CTLA-4封锁的背景下，阻断T细胞归巢会增加结肠炎的严重程度，而对肠管的贩运封锁对不同的Th亚群具有不同的影响，并且可以促进固有层（LP）中Th17细胞的增殖。我们的数据揭示了针对CTLA-4封锁诱发的结肠炎的贩运封锁抗体疗法的基本机制，并为在CTLA-4封锁条件下应用贩运封锁抗体治疗提供了警告。我们发现，在CTLA-4封锁的背景下，阻断T细胞归巢会增加结肠炎的严重程度，而对肠管的贩运封锁对不同的Th亚群具有不同的影响，并且可以促进固有层（LP）中Th17细胞的增殖。我们的数据揭示了针对CTLA-4封锁诱导的结肠炎的贩运封锁抗体疗法的基本机制，并为在CTLA-4封锁条件下应用贩运封锁抗体治疗提供了警告。我们发现，在CTLA-4封锁的背景下，阻断T细胞归巢会增加结肠炎的严重程度，而对肠管的贩运封锁对不同的Th亚群具有不同的影响，并且可以促进固有层（LP）中Th17细胞的增殖。我们的数据揭示了针对CTLA-4封锁诱导的结肠炎的贩运封锁抗体疗法的基本机制，并为在CTLA-4封锁条件下应用贩运封锁抗体治疗提供了警告。