title: Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma.
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.
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Diana
authors.affiliation: Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Lai Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Zenobia
authors.initials: Z
authors.lastname: D'Costa
authors.affiliation: Department of Pathology, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Allen
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Abul
authors.initials: A
authors.lastname: Azad
authors.affiliation: Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Department of Surgery, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Soonawalla
authors.affiliation: Department of Radiation Oncology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
authors.forename: Stanley
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: W Gillies
authors.initials: WG
authors.lastname: McKenna
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
mesh_terms: D000293:Adolescent; D000328:Adult; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CD8; Immune response; Immunity; Immunology and Microbiology Section; PD-1/PD-L1; immune; pancreatic cancer; prognosis