Immune profiling of deficient mismatch repair colorectal cancer (dMMR CRC) tumor microenvironment reveals different levels of immune system activation

Abstract To understand the immune landscape of deficient mismatch repair colorectal cancer (dMMR CRC) tumor microenviroment (TME), gene expression profiling was performed by the nCounter PanCancer Immune Profiling Panel. The study was conducted retrospectively on 89 dMMR-CRC samples. The expression of CD3, CD8, PD1 and PD-L1 protein was evaluated on a subset of samples by immunohistochemistry analysis, and lymphocyte density was calculated. A subset of deregulated genes was identified. Functional clustering analysis performed on these genes generated four main factors: factor 1, including antigen processing and presentation, with its MHC-II related genes; factor 2, comprising genes correlated with the cytotoxic activity of immune system; factor 3, T-Cell Chemotaxis/Cell Adhesion genes; and factor 4, T-CD4+ regulator cell-related genes. A “deregulation score” (DS), was calculated for each sample. Based on their DS, tumors were then classified as COLD (DS ≤ -3) to select the samples with a strong down-regulation of the immune system and NOTCOLD (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 homogenous group as concerns the immune system activity of TME. In particular, the distinction between COLD and NOTCOLD tumors may improve the management of these two subsets of patients.