Epithelial Notch1 drives metastasis by controlling neutrophil chemotaxis in a novel late stage colorectal cancer genetically engineered mouse model


Year:

Session type:

Theme:

Rene Jackstadt1
1CRUK Beatson Institute

Abstract

Background

Therapies currently available for late stage colorectal cancers (CRCs) are not highly effective. Myeloid cell populations have been indicated to play a crucial role during metastasis in other tumour entities like pancreatic and breast cancer as well as melanoma. In contrast, most pre-clinical studies of CRC have been performed in immune incompetent mice and/or as transplantation models.

Method

We have now generated novel immunocompetent highly metastatic (100%) Notch1 driven genetically engineered mouse models (GEMMs) of CRC which faithfully recapitulate the human CRC subtype with worse survival.

Results

Transcriptomic profiling of whole primary tumours shows high chemokine and neutrophil marker expression, which are associated with a high immunogenic micro-environment. Mechanistically, expression profiles reveal that Notch1 triggers epithelial Cxcl5 expression to control Cxcr2 positive neutrophil chemotaxis and eventually an increase in systemic neutrophil levels. Pharmacological inhibition of Cxcr2 positive neutrophils or neutrophil depletion, using a Cxcr2 small molecule or Ly6G blocking antibody, result in a significant reduction of distant metastases. Neutrophil inhibition leads to CD8+ T-cell infiltration indicating an immunosuppressive function of neutrophils in late stage CRC.

Conclusion

In sum, we can show that this new GEMM is a strong tool to investigate CRC immunotherapies, highlighted by the effect of Neutrophil inhibition on metastasis.