Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study

•HER2 expression was associated with epithelial markers, which have been associated with favorable outcomes.•HER2 expression was associated with lower expression of immune cell infiltration, but also lower expression of immune exhaustion markers.•Non-responders to HER2 targeting treatment demonstrated increased expression of immune exhaustion, as well as hypoxia and VEGF signaling. HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors. 84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2+n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2+n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value