Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
Organisms and Ecosystems, Earlham Institute, NR4 7UZ, Norwich, UK.
Nat Commun. 2023 Oct 23;14(1):6719. doi: 10.1038/s41467-023-41798-2.
Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.
免疫检查点抑制剂（CPIs）是一种相对较新的癌症治疗方法，使以前无法治疗的疾病现在有可能治愈。抗 CTLA4 和抗 PD-1 的联合方案显示出增强的疗效，但容易发生靶向免疫介导的组织损伤，特别是在屏障表面。为了研究免疫检查点对肠道稳态的影响，用抗 CTLA4 和抗 PD-1 免疫疗法和肠道微生物群操作来挑战小鼠。使用批量 RNA 测序、单细胞 RNA 测序和流式细胞术分析患有 CPI-结肠炎的小鼠结肠的免疫特征。小鼠的 CPI-结肠炎依赖于肠道微生物群的组成，并通过诱导表达干扰素-γ (IFNγ)、细胞毒性分子和其他促炎细胞因子/趋化因子的淋巴细胞。在阻断 IL23/IFNγ 轴后，这种 CPI-结肠炎的临床前模型可能会减弱。针对 IFNγ 产生淋巴细胞或调节网络的治疗靶向，可能是逆转 CPI-结肠炎的关键。
