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Pre-existing immunity drives the response to neoadjuvant chemotherapy in esophageal adenocarcinoma

ABSTRACT: Esophageal adenocarcinoma (EAC) is a highly aggressive tumor. Patients with locally advanced disease undergo neoadjuvant chemotherapy (nCT) before surgery, however fewer than 30% of treated patients achieve a pathological complete response associated with increased 5-year overall survival. We set out to elucidate the mechanisms the response to nCT by multi-dimensional profiling of pre-treatment tumor biopsies and blood samples from EAC patients. In particular we performed whole exome sequencing (WES) and RNAseq on n=26 baseline EAC tumor; two additional EAC samples underwent only WES. WES on matched peripheral blood mononuclear cells (PBMCs) were used as germline control.

PROVIDER: EGAS00001007245 | EGA |

REPOSITORIES: EGA

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Project description:Following exposure to chemoradiation, EAC cells increase their mitochondrial content and associated metabolic processes, which drives treatment resistance. Inhibition of this response using clinically applicable inhibitors of ESRRA in combination with (chemo)radiation shows promising anti-tumor activities and could be further developed for clinical use.

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

Project description: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.

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