Despite improvements in surgical oncology and precision medicine, 5-year survival rates for patients with advanced colorectal cancer (CRC) remain extremely poor. T-cell directed immunotherapies are only effective in around 5% of all CRC patients. Harnessing other cytotoxic cell types, such as NK cells may offer alternative therapeutic strategies. Here we used transcriptomic and multiplex immunohistochemistry approaches to evaluate the scope of NK cell heterogeneity in human CRC samples.
A CRC-specific NK cell gene signature which infers the NK cell load within individual tumours from bulk RNAseq data was designed and validated. Tumours with high evidence of this NK cell signature were characterised by the upregulation of chemotactic and cytolytic transcriptional programs. Furthermore, high NK scores in primary CRC samples were shown to have better survival outcomes in two independent cohorts. Focussing on metastatic disease, Cell type Identification by Estimating the Relative Subsets of RNA Transcripts (CIBERSORT) analysis revealed significant variance in terms of immune cell composition between Colorectal Liver Metastases (CRLM) and adjacent normal (AdjN) liver tissue. Using a novel mIHC panel to quantify the scope of NK cell infiltration and NK cell ligand expression, we found that neoadjuvant chemotherapy increased NK cell penetrance of CRLM tissue, restoring NK cell load to levels comparable with that found in the AdjN liver. Furthermore, NK cell densities were comparable in the AdjN liver and CRLM tissue of patients who partially responded to chemotherapy whereas non-responders showed preferential accumulation in the AdjN liver.
Collectively, our results further our understanding of tumour and immunological heterogeneity in primary CRC and CRLMs.