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 ZobniwChristine 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

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

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.

Original languageEnglish
Pages (from-to)509-523.e6
JournalCancer Cell
Volume40
Issue number5
DOIs
StatePublished - May 9 2022

Keywords

  • EAE
  • TC1/TC17
  • Th1/Th17
  • Th17 memory
  • arthritis
  • colitis
  • immune checkpoint blockade
  • immunity
  • interleukin-6
  • melanoma
  • toxicity

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