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

Abstract:

: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.

journal_name

EMBO Mol Med

journal_title

EMBO molecular medicine

authors

Germann M,Zangger N,Sauvain MO,Sempoux C,Bowler AD,Wirapati P,Kandalaft LE,Delorenzi M,Tejpar S,Coukos G,Radtke F

doi

10.15252/emmm.201910681

subject

Has Abstract

pub_date

2020-01-09 00:00:00

pages

e10681

issue

1

eissn

1757-4676

issn

1757-4684

journal_volume

12

pub_type

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