期刊
CANCER CELL
卷 40, 期 5, 页码 509-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2022.04.004
关键词
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资金
- Wilkes philanthropist fund
- Conquer Cancer Young Investigator Award
- NIH [K08AR079587, K01AI163412]
- Foundation for the NIH (FNIH)PACT
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- CPRIT [RP190326]
- NIH through the UT MDACC [CA016672]
- NIH CCSG grant [P30CA016672]
- National Cancer Institute of the National Institutes of Health [P50CA221703]
- IRG
Immune checkpoint blockade therapy can cause immune-related adverse events. IL-6 expression is higher in colitis and Th17 cells are more prevalent in immune-related enterocolitis. Anti-CTLA-4 induces stronger Th17 memory in colitis than anti-PD-1. In mouse models, IL-6 blockade enhances tumor control and increases CD4(+)/CD8(+) effector T cell density, while reducing Th17, macrophages, and myeloid cells. Combined IL-6 blockade and ICB enhances tumor rejection and mitigates EAE symptoms. IL-6 blockade with ICB can decouple autoimmunity from antitumor immunity.
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.
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