Oncotarget

Research Papers: Immunology:

Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

Angela Diana, Lai Mun Wang, Zenobia D’Costa, Paul Allen, Abul Azad, Michael A. Silva, Zahir Soonawalla, Stanley Liu, W. Gillies McKenna, Ruth J. Muschel and Emmanouil Fokas _

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Oncotarget. 2016; 7:40992-41004. https://doi.org/10.18632/oncotarget.10038

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Abstract

Angela Diana1,*, Lai Mun Wang2,*, Zenobia D’Costa1, Paul Allen2, Abul Azad1, Michael A. Silva3, Zahir Soonawalla3, Stanley Liu4, W. Gillies McKenna1, Ruth J. Muschel1 and Emmanouil Fokas1

1 Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK

2 Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK

3 Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK

4 Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada

* These are joint first authors

Correspondence to:

Emmanouil Fokas, email:

Keywords: PD-1/PD-L1, CD8, immune, prognosis, pancreatic cancer, Immunology and Microbiology Section, Immune response, Immunity

Received: April 20, 2016 Accepted: May 14, 2016 Published: June 14, 2016

Abstract

We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.


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