Targeting HDAC2-Mediated Immune Regulation to Overcome Therapeutic Resistance in Mutant Colorectal Cancer

SIMPLE SUMMARY: Epigenetic processes contribute to the regulation of the immune system by activating multiple transcriptional changes, which in turn, are the product of immune cell reprogramming. Given that the deregulation of these mechanisms promotes cancer progression by altering the balance of genes controlling cell proliferation and death, the objective of this study was to identify a genetic/epigenetic/immunological colorectal cancer signature through a preliminary in silico analysis aimed at identifying the pathogenic causes of colorectal cancer associated with expression levels of histone deacetylase 2 (HDAC2) and two immune system regulators, class II major histocompatibility complex transactivator (CIITA) and beta-2 microglobulin (B2M), in a cohort of patients harboring a common dysregulation of these genes. We next extended the study by investigating a tissue microarray cohort of colorectal cancer patients from a diagnostic/prognostic perspective. ABSTRACT: A large body of clinical and experimental evidence indicates that colorectal cancer is one of the most common multifactorial diseases. Although some useful prognostic biomarkers for clinical therapy have already been identified, it is still difficult to characterize a therapeutic signature that is able to define the most appropriate treatment. Gene expression levels of the epigenetic regulator histone deacetylase 2 (HDAC2) are deregulated in colorectal cancer, and this deregulation is tightly associated with immune dysfunction. By interrogating bioinformatic databases, we identified patients who presented simultaneous alterations in HDAC2, class II major histocompatibility complex transactivator (CIITA), and beta-2 microglobulin (B2M) genes based on mutation levels, structural variants, and RNA expression levels. We found that B2M plays an important role in these alterations and that mutations in this gene are potentially oncogenic. The dysregulated mRNA expression levels of HDAC2 were reported in about 5% of the profiled patients, while other specific alterations were described for CIITA. By analyzing immune infiltrates, we then identified correlations among these three genes in colorectal cancer patients and differential infiltration levels of genetic variants, suggesting that HDAC2 may have an indirect immune-related role in specific subgroups of immune infiltrates. Using this approach to carry out extensive immunological signature studies could provide further clinical information that is relevant to more resistant forms of colorectal cancer.