Non-coding genetic variants and microRNAs control gastric cancer immunogenicity

Abstract

Gastric cancer is one of the most common cancers worldwide and is usually diagnosed at a late stage due to the lack of early specific symptoms. Recently developed immunotherapeutic approaches have been successfully used to target advanced gastric cancer. The most used immunotherapeutic drugs against cancer are monoclonal antibodies targeting Programmed death-1 (PD-1) and Programmed death-ligand 1 (PD-L1), a glycoprotein overexpressed in many cancers promoting immune evasion. However, only a subset of patients responds to these therapies, while others experience severe immunological side effects or develop drug resistance. New biomarkers and combination therapies are needed to ensure effective and safe use of immunotherapeutic approaches. In this thesis, I identified a novel axis of regulation of PD-L1 expression in gastric cancer. Specifically, differential promoter methylation of a cancer-specific transcript of the chromosome X gene GABRA3 regulates the expression levels of the intronic microRNA (miRNA) miR-105-5p. miR-105-5p binds to the PD-L1 3 untranslated region (3-UTR) leading to downregulation of PD-L1 expression and tumor immunogenicity, as demonstrated by in vitro co-culture assays. More broadly, by analyzing hundreds of primary gastric cancer RNA sequencing (RNAseq data) I identified 3-UTR single nucleotide variants and short insertions/deletions that affect expression of immune-related genes in cis or are associated with changes in immune cell infiltration and other immune phenotypes in trans. This analysis identifies novel determinants of gastric cancer immunogenicity, such as Ribosomal Protein L38 (RPL38). These studies are significant as they point towards novel mechanisms of post-transcriptional regulation for important immunoediting genes and provide a resource for potential immunotherapeutic targets and biomarkers.