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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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Definition of a multi-omics signature for Esophageal Adenocarcinoma prognosis prediction [scRNA-seq]

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cfDNA methylation data of longitudinally collected blood plasma samples from patients with esophageal adenocarcinoma

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MicroRNA expression signatures in Barrett's esophagus and esophageal adenocarcinoma

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The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy

Project description:Immune checkpoint blockade has recently proven effective in a subset of patients with esophageal adenocarcinoma (EAC) but little is known regarding the EAC immune microenvironment. We determined the single cell transcriptional profile of EAC in patients who were treatment naive or had received neoadjuvant chemotherapy. Analysis of 52,387 cells revealed 10 major cell subsets of tumor, immune and stromal cells. Prior to chemotherapy tumors were characterised by infiltration with effector T cells showing markers of exhaustion together with large T regulatory cell infiltrates. Plasmacytoid dendritic cells were markedly expanded whilst two dominant cancer-associated fibroblast populations were observed. Pathological remission following chemotherapy was associated with broad reversal of immune abnormalities together with an increase in endothelial and myofibroblast populations although a chemoresistant epithelial stem cell population was apparent. These findings reveal features that underlie and limit the response to current immunotherapy and reveal a range of novel opportunities for targeted therapy.

2023-02-28 | GSE222078 | GEO

MicroRNA expression signatures in Barrett's esophagus and esophageal adenocarcinoma

Project description:Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that frequently develops from Barrett’s esophagus (BE), a premalignant pathological change occurring in the lower end of esophagus. To identify BE patients at high risk of malignant transformation is essential to the prevention of EAC. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of EAC have not been extensively evaluated.

2009-12-31 | GSE16456 | GEO

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