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

Author:

Zhou Yifan1ORCID,Medik Yusra B.1ORCID,Patel Bhakti1ORCID,Zamler Daniel B.23ORCID,Chen Sijie4ORCID,Chapman Thomas5ORCID,Schneider Sarah136ORCID,Park Elizabeth M.12ORCID,Babcock Rachel L.13ORCID,Chrisikos Taylor T.13ORCID,Kahn Laura M.13ORCID,Dyevoich Allison M.1ORCID,Pineda Josue E.13ORCID,Wong Matthew C.7ORCID,Mishra Aditya K.7ORCID,Cass Samuel H.5ORCID,Cogdill Alexandria P.123ORCID,Johnson Daniel H.8ORCID,Johnson Sarah B.5ORCID,Wani Khalida9ORCID,Ledesma Debora A.9ORCID,Hudgens Courtney W.9ORCID,Wang Jingjing5ORCID,Wadud Khan Md Abdul5ORCID,Peterson Christine B.310ORCID,Joon Aron Y.10ORCID,Peng Weiyi8ORCID,Li Haiyan S.1ORCID,Arora Reetakshi5ORCID,Tang Ximing9ORCID,Raso Maria Gabriela9ORCID,Zhang Xuegong4ORCID,Foo Wai Chin11ORCID,Tetzlaff Michael T.9ORCID,Diehl Gretchen E.12ORCID,Clise-Dwyer Karen6ORCID,Whitley Elizabeth M.13ORCID,Gubin Matthew M.1314ORCID,Allison James P.1314ORCID,Hwu Patrick38ORCID,Ajami Nadim J.27ORCID,Diab Adi8ORCID,Wargo Jennifer A.235714ORCID,Watowich Stephanie S.137ORCID

Affiliation:

1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 1

2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 2

3. The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 3

4. Ministry of Education Key Lab of Bioinformatics and Bioinformatics Division, Beijing National Research Center for Information Science and Technology; Department of Automation, Tsinghua University, Beijing, China 4

5. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 5

6. Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 6

7. Platform for Innovative Microbiome and Translational Research, MD Anderson Cancer Center, Houston, TX 7

8. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 8

9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 9

10. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 10

11. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 11

12. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 12

13. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 13

14. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 14

Abstract

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.

Funder

National Institutes of Health

Wilks Family Fund

Cancer Prevention and Research Institute of Texas

Parker Institute for Cancer Immunotherapy

University of Texas MD Anderson

National Heart, Lung, and Blood Institute

National Cancer Institute

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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