Interleukin-6 Blockade Abrogates Immunotherapy Toxicity and Promotes Tumor Immunity

Immune checkpoint blockade (ICB) for cancer is associated with high response rates but also high rates of adverse events. To elucidate the underlying immunobiology, we profiled gene expression in intestinal, colitis, and tumor tissue from ICB-treated patients, with parallel studies in preclinical models, and validated our findings in a review of clinical cohort treated with interleukin-6 blockade. Expression of interleukin-6, neutrophil and chemotactic markers was higher in colitis than in normal intestinal tissue. The genes upregulated in colitis were not upregulated in responding tumors from patients receiving ICB. In murine models, interleukin-6 blockade was 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 interleukin-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. Interleukin-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.