TY - JOUR
T1 - Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
AU - Zhou, Yifan
AU - Medik, Yusra B.
AU - Patel, Bhakti
AU - Zamler, Daniel B.
AU - Chen, Sijie
AU - Chapman, Thomas
AU - Schneider, Sarah
AU - Park, Elizabeth M.
AU - Babcock, Rachel L.
AU - Chrisikos, Taylor T.
AU - Kahn, Laura M.
AU - Dyevoich, Allison M.
AU - Pineda, Josue E.
AU - Wong, Matthew C.
AU - Mishra, Aditya K.
AU - Cass, Samuel H.
AU - Cogdill, Alexandria P.
AU - Johnson, Daniel H.
AU - Johnson, Sarah B.
AU - Wani, Khalida
AU - Ledesma, Debora A.
AU - Hudgens, Courtney W.
AU - Wang, Jingjing
AU - Khan, Md Abdul Wadud
AU - Peterson, Christine B.
AU - Joon, Aron Y.
AU - Peng, Weiyi
AU - Li, Haiyan S.
AU - Arora, Reetakshi
AU - Tang, Ximing
AU - Raso, Maria Gabriela
AU - Zhang, Xuegong
AU - Foo, Wai Chin
AU - Tetzlaff, Michael T.
AU - Diehl, Gretchen E.
AU - Clise-Dwyer, Karen
AU - Whitley, Elizabeth M.
AU - Gubin, Matthew M.
AU - Allison, James P.
AU - Hwu, Patrick
AU - Ajami, Nadim J.
AU - Diab, Adi
AU - Wargo, Jennifer A.
AU - Watowich, Stephanie S.
N1 - Publisher Copyright:
© 2022 Zhou et al.
PY - 2023/2/6
Y1 - 2023/2/6
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20221333
DO - 10.1084/jem.20221333
M3 - Article
C2 - 36367776
AN - SCOPUS:85141893961
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
M1 - e20221333
ER -