Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Precision Cancer Therapies Program, Department of Hematology and Medical Oncology, Ochsner Health, New Orleans, LA, USA.
Cancer Cell. 2022 May 9;40(5):509-523.e6. doi: 10.1016/j.ccell.2022.04.004.
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.
免疫检查点阻断 (ICB) 治疗经常会引发免疫相关的不良反应。为了阐明其潜在的免疫生物学机制，我们对接受 ICB 治疗的患者的肠道、结肠炎和肿瘤组织进行了深入的免疫分析，并在临床前模型中进行了平行研究。与正常肠道组织相比，结肠炎组织中白细胞介素 6 (IL-6)、中性粒细胞和趋化因子标志物的表达更高；与 T 辅助 1 (Th1) 细胞相比，免疫相关结肠炎 (irEC) 中 Th17 细胞更为常见。抗细胞毒性 T 淋巴细胞相关抗原 4 (抗 CTLA-4) 在结肠炎中诱导的 Th17 记忆比抗程序性死亡 1 (抗 PD-1) 更强。在小鼠模型中，与单独使用抗 PD-1 相比，阻断 IL-6 与改善肿瘤控制和更高密度的 CD4/CD8 效应 T 细胞相关，同时减少 Th17、巨噬细胞和髓样细胞。在伴有肿瘤的实验性自身免疫性脑脊髓炎 (EAE) 模型中，联合使用 IL-6 阻断和 ICB 可增强肿瘤排斥，同时减轻 EAE 症状，而单独使用 ICB 则不能。IL-6 阻断与 ICB 联合使用可能使自身免疫与抗肿瘤免疫脱钩。
