Germline and somatic determinants of the immune contexture in colorectal cancer

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Sillo, Toritseju Oluwafunmilayo ORCID: https://orcid.org/0000-0002-8600-7574 (2022). Germline and somatic determinants of the immune contexture in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Aims: Microsatellite instability is a recognised marker for determining the efficacy of immunotherapy in colorectal cancer (CRC). However, other immunogenomic markers could also drive the anti-tumour immune response. This thesis explores the hypothesis that both germline and somatic factors are significant in shaping the immune microenvironment in CRC. Associations were studied between germline immune gene expression quantitative trait loci (eQTLs) and a phenotypic marker of the tumour immune environment – the Immunoscore®. The somatic component focused on the contributions of tumour mutational burden, neoantigen clonality and the microbiome to the immune microenvironment.

Methods: This in silico analysis utilised genomic data and tumour samples from 200 patients with CRC enrolled in the 100 000 Genomes Project. From germline data, a panel of eQTLs was correlated with the Immunoscore using logistic regression. Somatic whole genome sequencing data was used to correlate tumour mutational burden (TMB) and neoantigen clonality with the Immunoscore. Metagenomic analysis was also performed on somatic data. Finally, RNA sequencing and immunohistochemistry on formalin-fixed tumour tissue were performed to corroborate these results.

Results: eQTLs associated with differences in the Immunoscore included TCF7, BCL11B, CCR1, CSK, IL19, IL23R and BCL10. While TMB was not significantly associated with the Immunoscore, a combination of neoantigen burden and neoantigen clonality (intratumoral heterogeneity) was strongly associated with the Immunoscore and clinical outcomes, independent of microsatellite status. RNA sequencing confirmed that the expression of major histocompatibility complex Class II genes, gut-bacteria-associated chemokines, and a T-helper centric metagene, were also all strongly associated with the Immunoscore.

Conclusions: Germline factors contribute to variability in the colorectal tumour immune contexture, particularly in MSS CRC. These effects are modulated by the contributions of somatic determinants, particularly the combination of neoantigen burden and clonality, which point to potential new biomarkers for determining the response to immunotherapy in colorectal cancer.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):