Neutrophils suppress tumor infiltrating T cells in colon cancer via matrix metalloproteinase mediated activation of TGF?

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 TGF?. CRC patient neutrophils similarly suppressed T cells via TGF? in vitro, and public gene expression datasets suggested that T cell activity is lowest in CRCs with combined neutrophil infiltration and TGF? activation. Thus, the interaction of neutrophils with a TGF?-rich tumor microenvironment may represent a conserved immunosuppressive mechanism in CRC.