Genome-wide differential genetic profiling characterizes colorectal cancers with genetic instability and specific routes to HLA class I loss and immune escape

Aim

We compared the expression of genes related to inflammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA? tumours and 6 MSS/HLA+ tumours (controls).

Findings

A first comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an Affymetrix^? HG-U133-Plus-PM plate, identified 1974 differentially expressed genes (P?P?=?5.5·10^?3), leucocyte activation (43 genes, P?=?1.8·10^?5), T-cell activation (24 genes, P?=?6.3·10^?4), inflammatory response (40 genes, 2.3·10^?2) and cytokine production (10 genes, P?=?1.9·10^?2). Real-time PCR and immunohistochemical evaluation were used to validate the data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+T lymphocytes in the MSI group (P?AP2, B2m) were downregulated in MSS/HLA-class I-negative CRCs (n?=?6) in comparison to controls.

Conclusions

In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour–host interactions and differentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked differences in the composition and intensity of infiltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.