Details

Autor(en) / Beteiligte

• Hailemichael, Yared
• Johnson, Daniel H.
• Abdel-Wahab, Noha
• Foo, Wai Chin
• Bentebibel, Salah-Eddine
• Daher, May
• Haymaker, Cara
• Wani, Khalida
• Saberian, Chantal
• Ogata, Dai
• Kim, Sang T.
• Nurieva, Roza
• Lazar, Alexander J.
• Abu-Sbeih, Hamzah
• Fa'ak, Faisal
• Mathew, Antony
• Wang, Yinghong
• Falohun, Adewunmi
• Trinh, Van
• Zobniw, Chrystia
• Spillson, Christine
• Burks, Jared K.
• Awiwi, Muhammad
• Elsayes, Khaled
• Soto, Luisa Solis
• Melendez, Brenda D.
• Davies, Michael A.
• Wargo, Jennifer
• Curry, Jonathan
• Yee, Cassian
• Lizee, Gregory
• Singh, Shalini
• Sharma, Padmanee
• Allison, James P.
• Hwu, Patrick
• Ekmekcioglu, Suhendan
• Diab, Adi

Titel

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity

Ist Teil von

• Cancer cell, 2022-05, Vol.40 (5), p.509-523.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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. [Display omitted] •Immunotherapy increases expression of Th17 and Tc17 cell differentiation cytokine IL-6•Th17 cells are more prevalent in enterocolitis than Th1•IL-6 blockade reduces Th17, increases Th1 and Tc1 cell density in ICB-treated tumors•Blockade of IL-6 decouples ICB antitumor immunity and toxicity Hailemichael et al. find that expression of interleukin-6, a Th17-cell differentiation cytokine, and neutrophil and chemotactic markers increase in inflamed tissue of patients and mice receiving immunotherapy. Blockade of IL-6 reduces Th17 and increases Th1 and CD8+ T effector cell density in tumor, mitigates ICB-induced autoimmunity, and potentiates antitumor immunity.