Immunotherapy is a new anti-cancer treatment option, showing promising results in clinical trials. To investigate potential immune-biomarkers in esophageal adenocarcinoma, we explored immune landscape patterns in the tumor microenvironment before and after neoadjuvant chemoradiation (nCRT). Sections from matched pre-treatment biopsies and post-nCRT resection specimens (n = 188) were stained for (i) programmed death-ligand 1 (PD-L1, CD274), (ii) programmed cell death protein 1 (PD-1, CD279), forkhead box P3 (FOXP3), CD8, pan-cytokeratin multiplex, and (iii) an MHC class I, II duplex. The densities of tumor associated immune cells (TAICs) were calculated using digital image analyses and correlated to histopathological nCRT-response (TRG), survival and post-nCRT immune patterns. PD-L1 positivity defined by combined positive score (CPS) of >1 was associated with a better response post-nCRT (TRG 1–3 versus 4,5, p = 0.010). In addition, high combined mean densities of CD8+, FOXP3+ and PD-1+ TAICs in the tumor-epithelium and stroma of biopsies were associated with better response (TRG 1–3 versus 4,5, p = 0.025 and p = 0.044, respectively). Heterogeneous TAIC density patterns were observed post-nCRT, with significantly higher CD8+ and PD-1+ TAIC mean densities compared to biopsies (both p = 0.000). Three immune landscape patterns were defined post-nCRT: ‘inflamed’, ‘invasive margin’ and ‘desert’, of which ‘inflamed’ was the most frequent (57%). Compared to matched biopsies, resection specimens with ‘inflamed’ tumors showed a significantly higher increase in CD8+ density compared to non-inflamed tumors post-nCRT (p = 0.000). In this cohort of esophageal adenocarcinoma patients, higher TAIC densities in pre-treatment biopsies associated with response to nCRT. This warrants future research into the potential of the tumor-immune landscape for patient stratification and novel (immune) therapeutic strategies.

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