Tumor-immune landscape patterns before and after chemoradiation in resectable esophageal adenocarcinomas

J Pathol. 2022 Mar;256(3):282-296. doi: 10.1002/path.5832. Epub 2021 Dec 10.


Immunotherapy is a new anti-cancer treatment option, showing promising results in clinical trials. To investigate potential immune biomarkers in esophageal adenocarcinoma (EAC), we explored immune landscape patterns in the tumor microenvironment before and after neoadjuvant chemoradiation (nCRT). Sections from matched pretreatment biopsies and post-nCRT resection specimens (n = 188) were stained for (1) programmed death-ligand 1 (PD-L1, CD274); (2) programmed cell death protein 1 (PD-1, CD279), forkhead box P3 (FOXP3), CD8, pan-cytokeratin multiplex; and (3) 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 [tumor regression grade (TRG)], survival, and post-nCRT immune patterns. PD-L1 positivity defined by a combined positive score 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 a 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 with 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 with matched biopsies, resection specimens with 'inflamed' tumors showed a significantly higher increase in CD8+ density compared with non-inflamed tumors post-nCRT (p = 0.000). In this cohort of EAC patients, higher TAIC densities in pretreatment biopsies were 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. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: PD-L1; biomarker; chemoradiotherapy; digital image analysis; esophageal adenocarcinoma; immunohistochemistry; treatment response; tumor-immune microenvironment; tumor-infiltrating lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemistry
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy*
  • Biomarkers, Tumor / analysis
  • CD8-Positive T-Lymphocytes / immunology*
  • Chemoradiotherapy, Adjuvant* / adverse effects
  • Databases, Factual
  • Esophageal Neoplasms / chemistry
  • Esophageal Neoplasms / immunology
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / therapy*
  • Esophagectomy* / adverse effects
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / adverse effects
  • Neoplasm Staging
  • Retrospective Studies
  • Time Factors
  • Treatment Outcome
  • Tumor Microenvironment / immunology*


  • Biomarkers, Tumor

Supplementary concepts

  • Adenocarcinoma Of Esophagus