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Immunity. 2019 Jan 15;50(1):166-180.e7. doi: 10.1016/j.immuni.2018.11.015.

Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer.

Author information

1
Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Personalized Medicine and Molecular Immunology, National Research Center - Institute of Immunology, FMBA, Moscow, 115478, Russia.
2
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
4
Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
5
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
6
University Duisburg-Essen, University Hospital, Institute for Experimental Immunology and Imaging, 45122 Essen, Germany.
7
Personalized Medicine and Molecular Immunology, National Research Center - Institute of Immunology, FMBA, Moscow, 115478, Russia.
8
Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA. Electronic address: sergey.grivennikov@fccc.edu.

Abstract

Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression.

KEYWORDS:

Cytokine; Interleukin 1; cell type specific signaling; colorectal cancer; microbiota; tumor elicited inflammation; tumor microenvironment

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