Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration

被引：33

作者：

Zhou, Yifan ^{[1
]}

Medik, Yusra B. ^{[1
]}

Patel, Bhakti ^{[1
]}

Zamler, Daniel B. ^{[2
,3
]}

Chen, Sijie ^{[4
,5
,6
]}

Chapman, Thomas ^{[7
]}

Schneider, Sarah ^{[1
,3
,8
]}

Park, Elizabeth M. ^{[1
,2
]}

Babcock, Rachel L. ^{[1
,3
]}

Chrisikos, Taylor T. ^{[1
,3
]}

Kahn, Laura M. ^{[1
,3
]}

Dyevoich, Allison M. ^{[1
]}

Pineda, Josue E. ^{[1
,3
]}

Wong, Matthew C. ^{[9
]}

Mishra, Aditya K. ^{[9
]}

Cass, Samuel H. ^{[7
]}

Cogdill, Alexandria P. ^{[1
,2
,3
]}

Johnson, Daniel H. ^{[10
]}

Johnson, Sarah B. ^{[7
]}

Wani, Khalida ^{[11
]}

Ledesma, Debora A. ^{[11
]}

Hudgens, Courtney W. ^{[11
]}

Wang, Jingjing ^{[7
]}

Wadud Khan, Md Abdul ^{[7
]}

Peterson, Christine B. ^{[3
,12
]}

Joon, Aron Y. ^{[12
]}

Peng, Weiyi ^{[10
]}

Li, Haiyan S. ^{[1
]}

Arora, Reetakshi ^{[7
]}

Tang, Ximing ^{[11
]}

Raso, Maria Gabriela ^{[11
]}

Zhang, Xuegong ^{[4
,5
,6
]}

Foo, Wai Chin ^{[13
]}

Tetzlaff, Michael T. ^{[11
]}

Diehl, Gretchen E. ^{[14
]}

Clise-Dwyer, Karen ^{[8
]}

Whitley, Elizabeth M. ^{[15
]}

Gubin, Matthew M. ^{[1
,3
,16
]}

Allison, James P. ^{[1
,3
,16
]}

Hwu, Patrick ^{[3
,10
]}

Ajami, Nadim J. ^{[2
,9
]}

Diab, Adi ^{[10
]}

Wargo, Jennifer A. ^{[2
,3
,7
,9
,16
]}

Watowich, Stephanie S. ^{[1
,3
,9
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX USA

[3] Univ Texas MD Anderson Canc Ctr, UTHlth Grad Sch Biomed Sci, Houston, TX 77030 USA

[4] Minist Educ, Beijing Natl Res Ctr Informat Sci & Technol, Key Lab Bioinformat, Beijing, Peoples R China

[5] Beijing Natl Res Ctr Informat Sci & Technol, Bioinformat Div, Beijing, Peoples R China

[6] Tsinghua Univ, Dept Automat, Beijing, Peoples R China

[7] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Hematopoiet Biol & Malignancy, Houston, TX USA

[9] MD Anderson Canc Ctr, Platform Innovat Microbiome & Translat Res, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Pathol, HOUSTON, TX USA

[14] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY USA

[15] UNIV TEXAS, MD ANDERSON CANC CTR,DEPT VET MED & SURG, HOUSTON, TX USA

[16] Univ Texas MD Anderson Canc Ctr, Parker Inst Canc Immunotherapy, Houston, TX USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2022年 / 220卷 / 02期

基金：

美国国家卫生研究院;

关键词：

ADVERSE EVENTS; CANCER; ANTI-CTLA-4; CELLS; STAT3; IMMUNOTHERAPY; HOMEOSTASIS; MECHANISMS; IPILIMUMAB; EXPRESSION;

D O I：

10.1084/jem.20221333

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 (alpha CTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found alpha CTLA-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 alpha CTLA-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 alpha CTLA-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 alpha CTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

引用

页数：31

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