![]() ![]() Myeloid cell-targeted and lymphocyte-targeted therapies can similarly promote both cytokines ( 7), and their induction is crucial in the rational design of cancer immunotherapeutics. These cytokines are characteristic of cell-mediated, T-helper 1 (Th1)-polarized immunity, and are appreciated as important in the body’s response to cancer. Interferon-gamma (IFN-□) and interleukin-12 (IL-12) induction accompany effective antitumor immune responses, both in mice ( 5– 8) and humans ( 9– 11). Toxicity appears to correlate with antitumor efficacy ( 3, 4) yet, whether similar or different mechanisms drive antitumor immunity and irAEs is largely unknown. Patients receiving immunotherapy for cancer can experience immune-related adverse events (irAEs) in normal, non-cancerous tissue, which frequently leads to discontinuation or disruption of therapy ( 1, 2). ![]() These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity. We observed activation of similar inflammatory pathways following anti-PD-1 and anti-CTLA4 immunotherapies in mice and humans. IL-12 and IFN-□ were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-□ and subsequently producing IL-12. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. ![]()
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