This thesis explores the immune microenvironment of primary and metastatic colorectal cancer.

In the first workstream, I examined the immune profile of colorectal pulmonary metastases and compared it to that of the primary in 34 matched primary-metastasis paired samples. I used whole-slide digital pathology scoring algorithms to characterise and quantify main immune cell infiltrates and ascertain their lineage and orientation. I also assessed expression levels of two key immune checkpoint blockade targets, PD-1 and PD-L1 as well as expression of MHC class I and II molecules. My results suggest that the microenvironment of pulmonary colorectal metastases is more immunologically active than that of the primary tumour with clear type 1 immunity signatures. This immunity however is supressed by overexpression of checkpoint blockade proteins.

The second workstream explored the microenvironment of a particular subgroup of mismatch repair proficient, microsatellite stable colorectal cancer which is characterised by upregulated coordinated immune response cluster (CIRC). This exploited a seven-plex immunofluorescence panel to stain for key immune markers and a digital pathology platform to phenotype and quantify them. The immune microenvironment of this group was then compared to those of mismatch repair deficient and proficient controls. The results revealed that this subgroup of tumours have comparable immune signatures to those of bona fide mismatch repair deficient tumours, suggestive of a heightened type 1 immunity.

Collectively, these findings highlight substantial intra and inter-patient heterogeneity in intra-tumoural immunity in colorectal cancer and have implications for development of targeted immunotherapies in the advanced cancer setting.