IL-6+髓系细胞浸润驱动anti-CTLA4诱导的肠道毒性
  • 在具有肠道验证遗传易感性、急性胃肠道感染、移植失调菌群或DSS诱导结肠炎的小鼠中,anti-CTLA4促进炎症和结肠组织损伤;
  • 鉴定出anti-CTLA4介导的免疫相关不良事件(irAE)的免疫特征,包括结肠中性粒细胞的积聚和全身IL-6的释放;
  • IL-6阻断联合抗生素治疗可减少炎症易发小鼠的肠道损伤,提高αCTLA-4的治疗效果;
  • 在ICB结肠炎患者的活检中,观察到相关的肠道免疫特征,即肠道浸润的中性粒细胞和活化的T细胞驱动了ICB相关的肠道毒性。
主编推荐语
章台柳
免疫检查点阻断治疗(ICB)在癌症治疗上取得巨大进展,但患者的生活质量和治疗的持续性受到免疫相关不良事件(irAE)的制约。Journal of Experimental Medicine近期发表的文章,构建了anti-CTLA4诱导肠道irAE的小鼠模型,并发现肠道浸润的中性粒细胞和活化的T细胞驱动了ICB相关的肠道毒性,IL-6阻断+抗生素治疗可提高anti-CTLA4的抗肿瘤效果,减少肠道损伤。
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Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration

CTLA-4阻断治疗诱导的肠道毒性是IL-6和髓系细胞浸润驱动的

10.1084/jem.20221333

2022-11-11, Article

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Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

First Authors:
Yifan Zhou

Correspondence Authors:
Stephanie S Watowich

All Authors:
Yifan Zhou,Yusra B Medik,Bhakti Patel,Daniel B Zamler,Sijie Chen,Thomas Chapman,Sarah Schneider,Elizabeth M Park,Rachel L Babcock,Taylor T Chrisikos,Laura M Kahn,Allison M Dyevoich,Josue E Pineda,Matthew C Wong,Aditya K Mishra,Samuel H Cass,Alexandria P Cogdill,Daniel H Johnson,Sarah B Johnson,Khalida Wani,Debora A Ledesma,Courtney W Hudgens,Jingjing Wang,Md Abdul Wadud Khan,Christine B Peterson,Aron Y Joon,Weiyi Peng,Haiyan S Li,Reetakshi Arora,Ximing Tang,Maria Gabriela Raso,Xuegong Zhang,Wai Chin Foo,Michael T Tetzlaff,Gretchen E Diehl,Karen Clise-Dwyer,Elizabeth M Whitley,Matthew M Gubin,James P Allison,Patrick Hwu,Nadim J Ajami,Adi Diab,Jennifer A Wargo,Stephanie S Watowich

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