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

// Martin Wartenberg 1, 2 , Inti Zlobec 2 , Aurel Perren 1, 2 , Viktor Hendrik Koelzer 1, 2 , Beat Gloor 3 , Alessandro Lugli 1, 2 , Eva Karamitopoulou 1, 2 1 Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland 2 Translational Research Unit, Institute of Pathology, University of Bern, Bern, CH-3010, Switzerland 3 Department of Visceral Surgery, Insel University Hospital, Bern, CH-3010, Switzerland Correspondence to: Eva Karamitopoulou, e-mail: eva.diamantis@pathology.unibe.ch Keywords: FOXP3, CD8, Tumor-associated macrophages, pancreatic cancer, prognosis, immune cell infiltration, epithelial mesenchymal transition, tumor budding, tumor microenvironment Received: August 28, 2014      Accepted: November 18, 2014      Published: February 10, 2015 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.