Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFβ

EMBO Mol Med. 2020 Jan 9;12(1):e10681. doi: 10.15252/emmm.201910681. Epub 2019 Dec 2.


High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to achieve broader immunotherapy responsiveness. Here, we investigated T cell-suppressive properties of different myeloid cell types in an inducible colon tumor mouse model. The most potent inhibitors of T-cell activity were tumor-infiltrating neutrophils. Gene expression analysis and combined in vitro and in vivo tests indicated that T-cell suppression is mediated by neutrophil-secreted metalloproteinase activation of latent TGFβ. CRC patient neutrophils similarly suppressed T cells via TGFβ in vitro, and public gene expression datasets suggested that T-cell activity is lowest in CRCs with combined neutrophil infiltration and TGFβ activation. Thus, the interaction of neutrophils with a TGFβ-rich tumor microenvironment may represent a conserved immunosuppressive mechanism in CRC.

Keywords: T-cell suppression; TGF-β; colorectal cancer; neutrophils; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colonic Neoplasms* / immunology
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Matrix Metalloproteinases / metabolism*
  • Mice
  • Neutrophils* / immunology
  • T-Lymphocytes / immunology*
  • Transforming Growth Factor beta / immunology*
  • Tumor Microenvironment


  • Transforming Growth Factor beta
  • Matrix Metalloproteinases

Associated data

  • GEO/GSE126874