The role of microvascular tumour endothelium in the recruitment of CD8+ T lymphocytes in colorectal cancer

Hepburn, Elizabeth Amanda (2017). The role of microvascular tumour endothelium in the recruitment of CD8+ T lymphocytes in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Tumour endothelial cells (TEC) display a distinct and angiogenic phenotype. They also permit trafficking of anti-tumour CD8+ T-lymphocytes into tumour stroma. I aimed to develop and validate an isolation technique and in vitro model of primary human colorectal TEC, characterize the TEC phenotype, and investigate intratumoural micro-environmental signals regulating CD8+ T-cell recruitment by TEC.
Flow cytometry, ELISA and QPCR revealed CD31, VWF, CD105, VEGFR’s, VE-Cadherin, CD13 and tumour specific marker TEM8 expression by colorectal TEC. TEC and tumour associated fibroblast (TAFB) produced higher concentrations of IL-6 and CCL2/MCP-1. Static and flow-based assays, demonstrated increased CD8+ T-cell adhesion by TEC and adhesion was augmented after conditioning with CRC derived TAFB supernatant. IL-6 and CCL2/MCP-1 blockade supressed CD8 T-cell adhesion. Endothelin-1 (ET1) was produced by TAFB and Endothelin Receptor B (ETB) was preferentially expressed by CRC endothelium, blockade of which, resulted in significantly increased ICAM-1 expression and CD8+ T-cell adhesion to TEC.
My validated in vitro TEC model confirms that CRC TEC has a unique phenotype influenced by the tumour microenvironment and that ETB inhibition may facilitate increased recruitment of CD8+ T-lymphocytes into the tumour stroma. This commands further investigation with the aim of developing an anti-cancer therapy in CRC.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):