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.
Sci Immunol. 2021 Jul 2;6(61). doi: 10.1126/sciimmunol.abi7083.
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 T1-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-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ 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 T1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
免疫疗法正在彻底改变癌症治疗方法，但它常常受到毒性的限制。人们对不良反应与伴随的抗肿瘤反应之间的区别了解甚少。在这里，我们使用抗 CD40 治疗在小鼠中作为促进 T1 的免疫治疗模型，结果表明肝巨噬细胞促进了局部免疫相关的不良反应。从机制上讲，组织驻留的库普弗细胞通过感应淋巴细胞衍生的 IFN-γ，随后产生 IL-12，介导肝毒性。相反，树突状细胞对于毒性不是必需的，但可以驱动肿瘤控制。IL-12 和 IFN-γ本身并不有毒，但促使中性粒细胞反应，从而决定组织损伤的严重程度。我们在小鼠和人类中观察到抗 PD-1 和抗 CTLA-4 免疫治疗后类似的炎症途径的激活。这些发现表明巨噬细胞和中性粒细胞是促进 T1 的免疫治疗中异常炎症的介质和效应物，提示毒性和抗肿瘤免疫的不同机制。
