Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma

Elizabeth Thompson, Marianna Zahurak, Adrian Murphy, Toby Cornish, Nathan Cuka, Eihab Abdelfatah, Stephen C Yang, Mark D Duncan, Nita Ahuja, Janis M Taube, Robert A Anders, Ronan Joseph Kelly

Research output: Contribution to journalArticle

Abstract

Objective Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastrooesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immunebased therapy.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - Jan 22 2016

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Stomach
Adenocarcinoma
Ligands
T-Lymphocytes
Esophagogastric Junction
Neoplasms
Survival
Cell Count
Human Herpesvirus 4
Disease-Free Survival
In Situ Hybridization
Histology
Immunohistochemistry
DNA
Therapeutics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. / Thompson, Elizabeth; Zahurak, Marianna; Murphy, Adrian; Cornish, Toby; Cuka, Nathan; Abdelfatah, Eihab; Yang, Stephen C; Duncan, Mark D; Ahuja, Nita; Taube, Janis M; Anders, Robert A; Kelly, Ronan Joseph.

In: Gut, 22.01.2016.

Research output: Contribution to journalArticle

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title = "Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma",
abstract = "Objective Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastrooesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results 12{\%} of resections showed tumour cell membranous PD-L1 expression and 44{\%} showed expression within the immune stroma. Two cases (6{\%}) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immunebased therapy.",
author = "Elizabeth Thompson and Marianna Zahurak and Adrian Murphy and Toby Cornish and Nathan Cuka and Eihab Abdelfatah and Yang, {Stephen C} and Duncan, {Mark D} and Nita Ahuja and Taube, {Janis M} and Anders, {Robert A} and Kelly, {Ronan Joseph}",
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AU - Thompson, Elizabeth

AU - Zahurak, Marianna

AU - Murphy, Adrian

AU - Cornish, Toby

AU - Cuka, Nathan

AU - Abdelfatah, Eihab

AU - Yang, Stephen C

AU - Duncan, Mark D

AU - Ahuja, Nita

AU - Taube, Janis M

AU - Anders, Robert A

AU - Kelly, Ronan Joseph

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Y1 - 2016/1/22

N2 - Objective Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastrooesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immunebased therapy.

AB - Objective Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastrooesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. Design Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. Results 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). Conclusions PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immunebased therapy.

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