Colitis is a common adverse effect of cancer therapy with checkpoint inhibitors, including those that target CTLA-4 signaling, and perturbations of the intestinal microbiome have been implicated in this pathology. Normal laboratory mice have not shed much light on this pathology as they are resistant to checkpoint-driven colitis, possibly owing to their restricted diet and microbiome. Research now published in Science uses C57BL/6 laboratory mice colonized with intestinal microbiota from wild-caught mice to establish a viable model for checkpoint inhibitor-induced colitis. Using these mice, the authors show that this colitis is dependent on IFNγ⁺CD4⁺ T cells and requires CTLA-4 blockade-induced depletion of intestinal peripheral regulatory T cells, effects that were absent in FcRγ-deficient mice. As a counter to this colitogenic mechanism, the authors applied anti-CTLA-4 nanobodies that lack an Fc domain to treat three different tumors in their mice. Both the nanobody and regular CTLA-4 antibodies were effective in limiting tumor growth and the tumor-infiltrating T cell phenotypes were not altered substantially in either case. By contrast, mice treated with CTLA-4 antibodies developed colitis, whereas those treated with the nanobody lacking an Fc domain did not.

结肠炎是检查点抑制剂（包括针对 CTLA-4 信号传导的抑制剂）癌症治疗的常见不良反应，而肠道微生物群的扰动与这种病理学有关。正常的实验室小鼠对这种病理学还没有太多了解，因为它们对检查点驱动的结肠炎具有抵抗力，这可能是由于它们的饮食和微生物组受到限制。现已发表在《科学》杂志上的研究使用 C57BL/6 实验小鼠，其肠道微生物群来自野生捕获的小鼠，以建立检查点抑制剂诱导的结肠炎的可行模型。作者利用这些小鼠表明，这种结肠炎依赖于 IFNγ ⁺ CD4 ⁺ T 细胞，并且需要 CTLA-4 阻断诱导肠道外周调节 T 细胞的消耗，而 FcRγ 缺陷小鼠中则没有这种效果。为了对抗这种致结肠炎机制，作者应用缺乏 Fc 结构域的抗 CTLA-4 纳米抗体来治疗小鼠中的三种不同肿瘤。纳米抗体和常规 CTLA-4 抗体均可有效限制肿瘤生长，并且肿瘤浸润 T 细胞表型在两种情况下均未发生实质性改变。相比之下，用 CTLA-4 抗体治疗的小鼠出现结肠炎，而用缺乏 Fc 结构域的纳米抗体治疗的小鼠则没有。