Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity,Cancer Cell

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Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity
Cancer Cell ( IF 50.3 ) Pub Date : 2022-05-09 , DOI: 10.1016/j.ccell.2022.04.004
Yared Hailemichael ₁ , Daniel H Johnson ₂ , Noha Abdel-Wahab ₃ , Wai Chin Foo ₄ , Salah-Eddine Bentebibel ₁ , May Daher ₅ , Cara Haymaker ₆ , Khalida Wani ₆ , Chantal Saberian ₁ , Dai Ogata ₁ , Sang T Kim ₇ , Roza Nurieva ₈ , Alexander J Lazar ₉ , Hamzah Abu-Sbeih ₁₀ , Faisal Fa'ak ₁ , Antony Mathew ₁₀ , Yinghong Wang ₁₀ , Adewunmi Falohun ₇ , Van Trinh ₁₁ , Chrystia Zobniw ₁₁ , Christine Spillson ₁ , Jared K Burks ₁₂ , Muhammad Awiwi ₁₃ , Khaled Elsayes ₁₃ , Luisa Solis Soto ₆ , Brenda D Melendez ₁ , Michael A Davies ₁ , Jennifer Wargo ₁₄ , Jonathan Curry ₄ , Cassian Yee ₁₅ , Gregory Lizee ₁₅ , Shalini Singh ₁₆ , Padmanee Sharma ₁₇ , James P Allison ₁₈ , Patrick Hwu ₁ , Suhendan Ekmekcioglu ₁ , Adi Diab ₁

Affiliation

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.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Section of Rheumatology & Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Rheumatology and Rehabilitation, Assiut University Hospitals, Faculty of Medicine, Assiut University, Egypt.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Section of Rheumatology & Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.

中文翻译：

白细胞介素 6 阻断消除免疫治疗毒性并促进肿瘤免疫

免疫检查点阻断 (ICB) 疗法经常诱发免疫相关的不良事件。为了阐明潜在的免疫生物学，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度免疫分析，并在临床前模型中进行了平行研究。白细胞介素 6 (IL-6)、中性粒细胞和趋化标志物在结肠炎中的表达高于正常肠组织；T 辅助细胞 17 (Th17) 细胞在免疫相关小肠结肠炎 (irEC) 中比 T 辅助细胞 1 (Th1) 更普遍。与抗程序死亡 1（抗 PD-1）相比，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 ^+相关效应 T 细胞，Th17、巨噬细胞和骨髓细胞减少。在具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，联合 IL-6 阻断和 ICB 可增强肿瘤排斥反应，同时减轻 EAE 症状。用 ICB 阻断 IL-6 可以将自身免疫与抗肿瘤免疫分离。

更新日期：2022-05-09

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