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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.

Wartenberg M, Zlobec I, Perren A, Koelzer VH, Gloor B, Lugli A, Karamitopoulou E - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus

CD8/Pancytokeratin double staining demonstrating a strong negative correlation between EMT-type tumor budding and CD8+T-cells(A and B) Examples of PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x100 (Bar:100 μm); (C and D) PDACs with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x100 (Bar:100 μm); (E) PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x400 (Bar:50μm); (F) PDAC with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x400 (Bar:50 μm).
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Figure 2: CD8/Pancytokeratin double staining demonstrating a strong negative correlation between EMT-type tumor budding and CD8+T-cells(A and B) Examples of PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x100 (Bar:100 μm); (C and D) PDACs with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x100 (Bar:100 μm); (E) PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x400 (Bar:50μm); (F) PDAC with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x400 (Bar:50 μm).

Mentions: A significant progressive increase in overall FOXP3+T-cell-counts and CD163-macrophages (M2) was found between normal pancreatic tissue, PanINs and PDACs (p = 0.0114, Figure 1, Table 1). The opposite was true for the CD8+T-cell infiltrates which were found to be markedly decreased in PDACs compared with normal tissues and PanINs (p < 0.0001, Table 1). These differences were more noticeable when taking into account the peritumoral/perilesional cell counts (p). Intraepithelial immune cell counts (i) were in general very low (Table 1). In PDACs a strong negative correlation between peritumoral CD8+T-cell counts and tumor budding was observed (p = 0.01, Figure 2).


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.

Wartenberg M, Zlobec I, Perren A, Koelzer VH, Gloor B, Lugli A, Karamitopoulou E - Oncotarget (2015)

CD8/Pancytokeratin double staining demonstrating a strong negative correlation between EMT-type tumor budding and CD8+T-cells(A and B) Examples of PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x100 (Bar:100 μm); (C and D) PDACs with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x100 (Bar:100 μm); (E) PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x400 (Bar:50μm); (F) PDAC with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x400 (Bar:50 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414182&req=5

Figure 2: CD8/Pancytokeratin double staining demonstrating a strong negative correlation between EMT-type tumor budding and CD8+T-cells(A and B) Examples of PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x100 (Bar:100 μm); (C and D) PDACs with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x100 (Bar:100 μm); (E) PDAC with numerous peritumoral CD8+T-cells and absence of tumor buds, x400 (Bar:50μm); (F) PDAC with high-grade tumor budding and markedly reduced peritumoral CD8+T-cell counts, x400 (Bar:50 μm).
Mentions: A significant progressive increase in overall FOXP3+T-cell-counts and CD163-macrophages (M2) was found between normal pancreatic tissue, PanINs and PDACs (p = 0.0114, Figure 1, Table 1). The opposite was true for the CD8+T-cell infiltrates which were found to be markedly decreased in PDACs compared with normal tissues and PanINs (p < 0.0001, Table 1). These differences were more noticeable when taking into account the peritumoral/perilesional cell counts (p). Intraepithelial immune cell counts (i) were in general very low (Table 1). In PDACs a strong negative correlation between peritumoral CD8+T-cell counts and tumor budding was observed (p = 0.01, Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pathology Division, University of Bern, Bern, CH-3010, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus