TY - JOUR
T1 - Tumor-immune landscape patterns before and after chemoradiation in resectable esophageal adenocarcinomas
AU - Soeratram, Tanya Td
AU - Creemers, Aafke
AU - Meijer, Sybren L
AU - de Boer, Onno J
AU - Vos, Wim
AU - van Berge Henegouwen, Mark I
AU - Hulshof, Maarten Ccm
AU - Bergman, Jacques Jghm
AU - Lei, Ming
AU - Bijlsma, Maarten F
AU - Ylstra, Bauke
AU - van Grieken, Nicole Ct
AU - van Laarhoven, Hanneke Wm
AU - Hooijer, Gerrit K J
N1 - Funding Information: This work was supported by the Dutch Cancer Society (KWF 10613/2016‐2). Publisher Copyright: © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - PD-L1
KW - biomarker
KW - chemoradiotherapy
KW - digital image analysis
KW - esophageal adenocarcinoma
KW - immunohistochemistry
KW - treatment response
KW - tumor-immune microenvironment
KW - tumor-infiltrating lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=85120880283&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/path.5832
DO - https://doi.org/10.1002/path.5832
M3 - Article
C2 - 34743329
SN - 0022-3417
VL - 256
SP - 282
EP - 296
JO - Journal of pathology
JF - Journal of pathology
IS - 3
ER -