Siwicki et al. used a CD40 agonist mouse lung tumor model to investigate TH1-driven IL-12 and IFNγ toxicity in non-tumor-bearing liver tissue. In tumor-bearing mice treated with agonist CD40, liver-resident Kupfer cells were activated by increased levels of immune cell-produced IFNγ, stimulating IL-12 production and cooperative augmentation of liver damage. Dendritic cells were required for tumor control, but were not responsible for toxicity. Mechanistically, IFNγ, IL-12, and macrophages induced a toxic neutrophil response that correlated with tissue damage. Similar pathways were observed in humans treated with immunotherapy (anti-PD-1 or anti-PD-1 plus anti-CTLA-4).
Contributed by Katherine Turner
ABSTRACT: Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T(H)1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-_ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-_ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T(H)1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
Author Info: (1) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (2) Department of Systems Biology, Harvard Medical Sc
Author Info: (1) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (2) Department of Systems Biology, Harvard Medical School, Boston, MA, USA. (3) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (4) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (5) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (6) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (7) Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania. (8) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (9) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (10) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (11) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (12) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (13) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. (14) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. (15) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (16) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (17) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (18) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (19) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (20) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (21) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. (22) Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. (23) Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (24) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. (25) Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. Swiss Cancer Center Leman (SCCL), Lausanne and Geneva, Switzerland. (26) Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. Division of Clinical Pathology, Geneva University Hospital, Geneva, Switzerland. (27) Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland. (28) Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland. (29) Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. Service of Gastroenterology and Hepatology, Lausanne University Hospital, Lausanne, Switzerland. (30) Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland. (31) Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (32) Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. Swiss Cancer Center Leman (SCCL), Lausanne and Geneva, Switzerland. (33) Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland. (34) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. (35) Department of Systems Biology, Harvard Medical School, Boston, MA, USA. (36) Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. mikael.pittet@unige.ch. Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. Department of Oncology, Geneva University Hospitals, Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. Swiss Cancer Center Leman (SCCL), Lausanne and Geneva, Switzerland.
