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

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 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.

SUBMITTER: Markus Germann

PROVIDER: S-SCDT-EMM-2019-10681 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundFollowing an acute insult, macrophages regulate renal fibrogenesis through the release of various factors that either encourage the synthesis of extracellular matrix synthesis or the degradation of matrix via endocytosis, proteolysis, or both. However, the roles of infiltrating versus resident myeloid cells in these opposing processes require elucidation. The transcription factor Twist1 controls diverse essential cellular functions through induction of several downstream targets, including matrix metalloproteinases (MMPs). In macrophages, Twist1 can influence patterns of cytokine generation, but the role of macrophage Twist1 in renal fibrogenesis remains undefined.MethodsTo study Twist1 functions in different macrophage subsets during kidney scar formation, we used two conditional mutant mouse models in which Twist1 was selectively ablated either in infiltrating, inflammatory macrophages or in resident tissue macrophages. We assessed fibrosis-related parameters, matrix metallopeptidase 13 (MMP13, or collagen 3, which catalyzes collagen degradation), inflammatory cytokines, and other factors in these Twist1-deficient mice compared with wild-type controls after subjecting the animals to unilateral ureteral obstruction. We also treated wild-type and Twist1-deficient mice with an MMP13 inhibitor after unilateral ureteral obstruction.ResultsTwist1 in infiltrating inflammatory macrophages but not in resident macrophages limited kidney fibrosis after ureteral obstruction by driving extracellular matrix degradation. Moreover, deletion of Twist1 in infiltrating macrophages attenuated the expression of MMP13 in CD11b+Ly6Clo myeloid cells. Inhibition of MMP13 abrogated the protection from renal fibrosis afforded by macrophage Twist1.ConclusionsTwist1 in infiltrating myeloid cells mitigates interstitial matrix accumulation in the injured kidney by promoting MMP13 production, which drives extracellular matrix degradation. These data highlight the complex cell-specific actions of Twist1 in the pathogenesis of kidney fibrosis.

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

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