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.
Highlights
High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response
A–C Evaluation of TGFb signaling activity in mouse colon tumors after four consecutive daily injections of hosts with 40 mg/kg of the MMP2/9-inhibitor SB3-CT (MMPi). (A and B) Co-immunostaining for pSMAD3 and IGFBP7 on representative tumor-containing colon sections derived from Apcfl/fl-Cdx2CreERT2 mice treated with vehicle (A) or MMPi (B). (C) Quantification of pSMAD3+ cells and pSMAD3 staining intensity per pSMAD3+ cell on at least five arbitrarily selected tumor areas per section of MMPi (n = 6)- or vehicle (n = 6)-treated mice
Apcfl/fl-Cdx2CreERT2 mice were treated with Tamoxifen and, 1 day post-treatment, injected with either MMPi (n = 10) or the TGFBRi SB431542 (n = 10) at 40 mg/kg for 2 weeks with five injections per week
Summary
High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. T cellmediated anti-tumor immune response correlates with favorable disease outcome and is the basis of cancer immunotherapy (Angell & Galon, 2013; Ribas & Wolchok, 2018). Many myeloid cells, such as macrophages, dendritic cells, monocytes, and neutrophils, act as antigen presenting cells to promote anti-tumor T-cell responses, and suppress T cells in many cancer contexts (Grivennikov et al, 2010; Joyce & Fearon, 2015; Kumar et al, 2016). We found that neutrophil infiltration is a conserved feature of human CRCs and that concomitant neutrophil infiltration plus TGFb activation is indicative of T-cell suppression in human tumors
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