title: Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma.
abstract: Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC). CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+-macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome. Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB. PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3.
authors: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.|Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Martin
authors: M
authors: Wartenberg
authors: Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Inti
authors: I
authors: Zlobec
authors: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.|Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Aurel
authors: A
authors: Perren
authors: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.|Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Viktor Hendrik
authors: VH
authors: Koelzer
authors: Department of Visceral Surgery, Insel University Hospital, Bern, CH-3010, Switzerland.
authors: Beat
authors: B
authors: Gloor
authors: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.|Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Alessandro
authors: A
authors: Lugli
authors: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.|Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland.
authors: Eva
authors: E
authors: Karamitopoulou
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D015331:Cohort Studies; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D060787:Neoplasm Grading; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D010641:Phenotype; D011379:Prognosis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors