microRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Anti-tumor Immune Response and Poor Outcomes of Patients. microRNA 125a Regulates MHC-I Expression on Esophageal Adenocarcinoma Cells, Associated With Suppression of Anti-tumor Immune Response and Poor Outcomes of Patients

BACKGROUND & AIMS: Immune checkpoint inhibition may affect outcomes of highly aggressive cancers, such as esophageal adenocarcinoma (EAC). In this regard, the MHC-I pathway and the tumor immune microenvironment are key factors that need to be explored. METHODS: We investigated post-transcriptional mechanisms of MHC-I regulation through functional and molecular studies of EAC cell lines and of EAC biopsies. We performed RNA-sequencing of fifty-one treatment-naïve EAC biopsies to evaluate the status of the MHC-I pathway and the tumor immune microenvironment with respect to patient response and disease outcomes. RESULTS: We found that in EAC miR-125a-5p and miR-148a-3p regulate TAP2 and MHC-I expression. Interestingly, MHC-I pathway expression correlated with poorer therapeutic response. Moreover, MHC-I status correlated with a tumor immune-inflamed microenvironment, in which upregulation of PD-L1, PD-L2 and IDO1 were associated to worse patient survival. CONCLUSIONS: Our data indicate that EAC patients with a proficient MHC-I expression and a tumor immune-inflamed microenvironment have poorer outcomes after neo-adjuvant therapy and may benefit from immune checkpoint inhibition. Overall design: We performed RNA-sequencing of fifty-one treatment-naïve EAC biopsies