Immune Profiling of Deficient Mismatch Repair Colorectal Cancer Tumor Microenvironment Reveals Different Levels of Immune System Activation

Abstract

To understand the immune landscape of deficient mismatch repair colorectal cancer (dMMR CRC) tumor microenvironment, gene expression profiling was performed by the nCounter PanCancer Immune Profiling Panel. This study was conducted retrospectively on 89 dMMR-CRC samples. The expression of CD3, CD8, programmed death-1, and programmed death ligand-1 protein was evaluated on a subset ofsamples by immunohistochemistry, and lymphocyte density was calculated. A subset of deregulated genes was identified. Functional clustering analysis performed on these genes generated four main factors: antigen processing and presentation, with its major histocompatibility complex-II-related genes; genes correlated with the cytotoxic activity of immune system; T-cell chemotaxis/cell adhesion genes; and T-CD4+ regulator cell-related genes. A deregulation score (DS)was calculated for each sample. On the basis of their DS, tumors were then classified as COLD (DS≤-3) to select the samples with a strong down-regulation of the immune system and NOT COLD (DS≥-2). The COLD group of patients showed a worse prognosis in terms of survival considering all patients (P=0.0172) and patients with metastatic disease (P=0.0031). These results confirm that dMMR-CRCs do not constitute a homogeneous group as concerns the immune system activity of tumor microenvironment. In particular, the distinction between COLD and NOT COLD tumors may improve the management of these two subsets of patients.