美国德州大学MD安德森癌症中心Adi Diab研究小组最近取得了重要工作进展，他们研究发现白细胞介素-6（IL-6）阻断可消除免疫治疗毒性并促进肿瘤免疫。该研究2022年5月9日在线发表于《癌细胞》杂志上。

为了阐明潜在的免疫生物学机理，研究人员对免疫检查点阻断 (ICB) 治疗患者的肠道、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。结肠炎组织中白细胞介素-6 (IL-6)、中性粒细胞和趋化标志物的表达高于正常肠组织；T辅助细胞17 (Th17) 在免疫相关小肠结肠炎（irEC）中比T辅助1（Th1）更普遍。与抗程序性死亡1（anti-PD-1）相比，抗细胞毒性T淋巴细胞相关抗原4（anti-CTLA-4）在结肠炎中诱导更强的Th17记忆。

在小鼠模型中，IL-6阻断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、巨噬细胞和骨髓细胞。在带有肿瘤的实验性自身免疫性脑脊髓炎（EAE）模型中，与单独使用ICB相比，IL-6阻断和ICB联合使用可增强肿瘤排斥，同时减轻EAE症状。用ICB阻断IL-6可使自身免疫与抗肿瘤免疫脱钩。

据了解，免疫检查点阻断 (ICB) 治疗经常诱发免疫相关的不良事件。

附：英文原文

Title: Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Author: Yared Hailemichael, Daniel H. Johnson, Noha Abdel-Wahab, Wai Chin Foo, Salah-Eddine Bentebibel, May Daher, Cara Haymaker, Khalida Wani, Chantal Saberian, Dai Ogata, Sang T. Kim, Roza Nurieva, Alexander J. Lazar, Hamzah Abu-Sbeih, Faisal Faak, Antony Mathew, Yinghong Wang, Adewunmi Falohun, Van Trinh, Chrystia Zobniw, Christine Spillson, Jared K. Burks, Muhammad Awiwi, Khaled Elsayes, Luisa Solis Soto, Brenda D. Melendez, Michael A. Davies, Jennifer Wargo, Jonathan Curry, Cassian Yee, Gregory Lizee, Shalini Singh, Padmanee Sharma, James P. Allison, Patrick Hwu, Suhendan Ekmekcioglu, Adi Diab

Issue&Volume: 2022/05/09

Abstract: Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverseevents. To elucidate the underlying immunobiology, we performed a deep immune analysisof intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studiesin preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotacticmarkers 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 Th17memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockadeassociated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimentalautoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICBenhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone.IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

DOI: 10.1016/j.ccell.2022.04.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00166-0