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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis
  • Cells, Cultured
  • Colorectal Neoplasms / immunology*
  • Humans
  • Inflammation / metabolism*
  • Interleukin-1 / genetics
  • Interleukin-1 / immunology
  • Interleukin-1 / metabolism*
  • Interleukin-17 / metabolism*
  • Interleukins / metabolism
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology*
  • Neutrophils / ultrastructure
  • Organ Specificity
  • Receptors, Interleukin-1 / genetics
  • Salmonella / immunology*
  • Salmonella Infections, Animal / immunology*
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • Interleukin-1
  • Interleukin-17
  • Interleukins
  • Receptors, Interleukin-1
  • interleukin-22