Exploring immunogenomic influences on the microenvironment of colorectal cancer

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Lal, Neeraj (2017). Exploring immunogenomic influences on the microenvironment of colorectal cancer. University of Birmingham. Ph.D.

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Abstract

This thesis focussed on the immunobiology of colorectal cancer (CRC). It explored the role of the γδ T cell ligand Endothelial Protein C Receptor (EPCR) in tumourigenesis, and subsequently characterised the relationship between intra-tumoural immunity and tumour genetics. In silico analyses and immunohistochemistry indicated EPCR was commonly overexpressed in epithelial cancers including CRC. EPCR was upregulated due to gene amplification and DNA hypomethylation alongside neighbouring genes on chromosome 20q, a region previously implicated in tumourigenesis. These results clarify why EPCR is upregulated in diverse epithelial malignancies, with implications for EPCR-focussed clinical studies and understanding of γδ T cell immunity.

TCGA analyses revealed that a novel immune signature, termed The Co-ordinate Immune Response Cluster (CIRC), comprising 28 genes, was co-ordinately regulated across CRC patients. Four patient subgroups were delineated based on CIRC expression. Microsatellite instability and POLE/POLD1 mutations were associated with high mutational burden and immune infiltration. Immune checkpoint molecules were highly co-ordinated in expression. RAS mutation was associated with lower CIRC expression. Further analyses revealed that RAS-associated immunosuppression was greatest in the most immunosuppressed transcriptional subtype, CMS2. These findings have implications for design of stratified immunotherapy approaches and highlight factors contributing to the particularly poor outcome of RAS mutant CRC.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):