Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Yared Hailemichael; Daniel H Johnson; Noha Abdel-Wahab; Wai Chin Foo; Salah-Eddine Bentebibel; May Daher; Cara Haymaker; Khalida Wani; Chantal Saberian; Dai Ogata; Sang T Kim; Roza Nurieva; Alexander J Lazar; Hamzah Abu-Sbeih; Faisal Fa'ak; Antony Mathew; Yinghong Wang; Adewunmi Falohun; Van Trinh; Chrystia Zobniw; Christine Spillson; Jared K Burks; Muhammad Awiwi; Khaled Elsayes; Luisa Solis Soto; Brenda D Melendez; Michael A Davies; Jennifer Wargo; Jonathan Curry; Cassian Yee; Gregory Lizee; Shalini Singh; Padmanee Sharma; James P Allison; Patrick Hwu; Suhendan Ekmekcioglu; Adi Diab

doi:10.1016/j.ccell.2022.04.004

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Cancer Cell. 2022 May 9;40(5):509-523.e6. doi: 10.1016/j.ccell.2022.04.004. Epub 2022 May 9.

Authors

Yared Hailemichael¹, Daniel H Johnson², Noha Abdel-Wahab³, Wai Chin Foo⁴, Salah-Eddine Bentebibel¹, May Daher⁵, Cara Haymaker⁶, Khalida Wani⁶, Chantal Saberian¹, Dai Ogata¹, Sang T Kim⁷, Roza Nurieva⁸, Alexander J Lazar⁹, Hamzah Abu-Sbeih¹⁰, Faisal Fa'ak¹, Antony Mathew¹⁰, Yinghong Wang¹⁰, Adewunmi Falohun⁷, Van Trinh¹¹, Chrystia Zobniw¹¹, Christine Spillson¹, Jared K Burks¹², Muhammad Awiwi¹³, Khaled Elsayes¹³, Luisa Solis Soto⁶, Brenda D Melendez¹, Michael A Davies¹, Jennifer Wargo¹⁴, Jonathan Curry⁴, Cassian Yee¹⁵, Gregory Lizee¹⁵, Shalini Singh¹⁶, Padmanee Sharma¹⁷, James P Allison¹⁸, Patrick Hwu¹, Suhendan Ekmekcioglu¹, Adi Diab¹⁹

Affiliations

¹ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Precision Cancer Therapies Program, Department of Hematology and Medical Oncology, Ochsner Health, New Orleans, LA, USA.
³ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Section of Rheumatology & Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Rheumatology and Rehabilitation, Assiut University Hospitals, Faculty of Medicine, Assiut University, Egypt.
⁴ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Section of Rheumatology & Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA.
⁹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
¹⁰ Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹² Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
¹⁵ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁶ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁷ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁸ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁹ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: [email protected].

Abstract

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4⁺/CD8⁺ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

Trial registration: ClinicalTrials.gov NCT04940299.

Keywords: EAE; TC1/TC17; Th1/Th17; Th17 memory; arthritis; colitis; immune checkpoint blockade; immunity; interleukin-6; melanoma; toxicity.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Colitis* / chemically induced
Humans
Immunologic Factors / therapeutic use
Immunotherapy
Interleukin-6
Mice
Myeloid Cells
Neoplasms* / drug therapy

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

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