Abstract 5545: Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
Abstract 5545: Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
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摘要 5545：IL-6 和骨髓浸润驱动的 CTLA-4 阻断的肠道毒性
DOI：
10.1158/1538-7445.am2022-5545
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发表时间：
2022
期刊：
影响因子：
11.2
通讯作者：
S. Watowich
中科院分区：
文献类型：
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作者：
Yifan Zhou;Yusra B Medik;B. Patel;D. Zamler;Sijie Chen;T. Chapman;Sarah Schneider;Rachel L. Babcock;Taylor T. Chrisikos;Laura M. Kahn;Allison M. Dyevoich;E. Park;Alexandria P. Cogdill;Daniel H Johnson;Sarah B. Johnson;K. Wani;D. Ledesma;C. Hudgens;Jingjing Wang;M. A. W. Khan;Aron Y Joon;W. Peng;Haiyan S. Li;R. Arora;Ximing Tang;M. G. Raso;Xuegong Zhang;W. Foo;M. Tetzlaff;G. Diehl;K. Clise;Elizabeth M Whitley;M. Gubin;J. Allison;P. Hwu;N. Ajami;A. Diab;J. Wargo;S. Watowich
免疫疗法如抗CTLA-4免疫检查点阻断（ICB）已经彻底改变了癌症治疗，但生活质量和治疗的持续性可能受到脱靶组织损伤或免疫相关不良事件（irAE）的限制。目前，对irAE机制的了解有限，阻碍了减轻其损害的方法的发展。我们通过产生肠道irAE的动物模型来解决这个问题。我们的研究结果表明，肠道炎症或急性胃肠道感染的遗传易感性破坏稳态免疫使小鼠对抗CTLA-4介导的肠道毒性敏感。用抗CTLA-4治疗的炎症倾向小鼠显示中性粒细胞积聚、全身性白细胞介素-6（IL-6）释放和生态失调。值得注意的是，IL-6阻断联合抗生素治疗改善了抗CTLA-4治疗效果并减少了肠道irAE。在ICB期间发生结肠炎的患者的活检中验证了免疫特征，支持我们模型的实用性。本研究提供了新的临床前模型、对irAE的机制见解以及在减轻irAE的同时增强ICB疗效的潜在方法。
引文格式：Yifan Zhou，Yusra B.麦迪克，巴克提·帕特尔，丹尼尔，B.放大图片作者：Zamler，Sijie Chen，托马斯查普曼，Sarah Schneider，Rachel L.作者：Taylor T.作者：Christikos，Laura M.放大图片作者：Allison M.作者：Elizabeth M.放大图片作者：丹尼尔H.约翰逊，莎拉B。作者：约翰逊作者：瓦尼Courtney W. Ledesma放大图片创作者：王晶晶，王伟.作者：Joon，Weiyi Peng，Haiyan S. Li，Reetakshi Arora，Ximing Tang，Maria Gabriela Raso，Xuegong Zhang，阿威Chin Foo，Michael T.作者声明：E.放大图片作者：Elizabeth M.作者：Whitley，Matthew M.放大图片作者：古宾，詹姆斯P.艾利森，帕特里克胡，纳迪姆J. Stephanie S. Wargo瓦托维奇由IL-6和骨髓浸润驱动的CTLA-4阻断的肠道毒性[摘要]。在：美国癌症研究协会年会论文集2022; 2022年4月8日至13日。Philadelphia（PA）：AACR; Cancer Res 2022;82（12_Suppl）：Abstract nr 5545.
Immunotherapies such as anti-CTLA-4 immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by off-target tissue damage or immune-related adverse events (irAEs). At present, there is limited understanding of irAE mechanisms, hampering development of approaches to mitigate their damage. We addressed this problem by generating animal models of intestinal irAE. Our results show that disruption of homeostatic immunity by genetic predisposition to intestinal inflammation or acute gastrointestinal infection sensitizes mice to anti-CTLA-4-mediated intestinal toxicity. Inflammation-prone mice treated with anti-CTLA-4 showed neutrophil accumulation, systemic interleukin-6 (IL-6) release, and dysbiosis. Significantly, IL-6 blockade combined with antibiotic treatment improved anti-CTLA-4 therapeutic efficacy and reduced intestinal irAEs. Immune signatures were validated in biopsies from patients who developed colitis during ICB, supporting the utility of our models. This study provides new pre-clinical models, mechanistic insight into irAEs, and potential approaches to enhance ICB efficacy while mitigating irAEs.
Citation Format: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, 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. Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5545.