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.

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.

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

MeSH terms

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

Substances

  • Immunologic Factors
  • Interleukin-6