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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

Snapshots of the tumor microenvironment of PDAC demonstrating tumor budding cells surrounded by numerous FOXP3+T-cells (A, x400, Bar:50μm); moderate counts of CD4+T-cells (B, x400, Bar:50μm); isolated iNOS-macrophages (C, x400, Bar:50μm) and dense infiltrates of CD163-macrophages (D, x400, Bar:50μm)
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Figure 3: Snapshots of the tumor microenvironment of PDAC demonstrating tumor budding cells surrounded by numerous FOXP3+T-cells (A, x400, Bar:50μm); moderate counts of CD4+T-cells (B, x400, Bar:50μm); isolated iNOS-macrophages (C, x400, Bar:50μm) and dense infiltrates of CD163-macrophages (D, x400, Bar:50μm)

Mentions: Results for all markers for associations with clinicopathological features when considering all patients and using the median normalized cell counts are summarized in Suppl. Table 2. Representative examples of the immune cell infiltrates in the microenvironment of PDAC are depicted in the Figures 2 and 3. Increased peritumoral FOXP3+T-cell-counts (FOXP3p) correlated with high-grade tumor budding including budding 10-in-10 (p = 0.0425) previously assessed in whole tissue sections, as well as ITB (p = 0.0428) and PTB (p < 0.0001), assessed at the TMA spots for each protein and showed significant correlation with the presence of venous invasion (p = 0.0189), distant metastasis (p = 0.0073) and positive resection margins (p = 0.0067) (Table 2). Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion (p = 0.0062), N-stage (p = 0.0022) and PTB (p = 0.0041, Table 2). High peritumoral CD163-counts (CD163p) correlated with venous invasion (p = 0.0291), budding 10-in-10 (p = 0.0155), PTB (p = 0.0200) and ITB (p = 0.0253, Table 3). High intratumoral CD163-counts (CD163i) correlated significantly with T-stage (p = 0.006) and PTB (p = 0.0349, Table 3).


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)

Snapshots of the tumor microenvironment of PDAC demonstrating tumor budding cells surrounded by numerous FOXP3+T-cells (A, x400, Bar:50μm); moderate counts of CD4+T-cells (B, x400, Bar:50μm); isolated iNOS-macrophages (C, x400, Bar:50μm) and dense infiltrates of CD163-macrophages (D, x400, Bar:50μm)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Snapshots of the tumor microenvironment of PDAC demonstrating tumor budding cells surrounded by numerous FOXP3+T-cells (A, x400, Bar:50μm); moderate counts of CD4+T-cells (B, x400, Bar:50μm); isolated iNOS-macrophages (C, x400, Bar:50μm) and dense infiltrates of CD163-macrophages (D, x400, Bar:50μm)
Mentions: Results for all markers for associations with clinicopathological features when considering all patients and using the median normalized cell counts are summarized in Suppl. Table 2. Representative examples of the immune cell infiltrates in the microenvironment of PDAC are depicted in the Figures 2 and 3. Increased peritumoral FOXP3+T-cell-counts (FOXP3p) correlated with high-grade tumor budding including budding 10-in-10 (p = 0.0425) previously assessed in whole tissue sections, as well as ITB (p = 0.0428) and PTB (p < 0.0001), assessed at the TMA spots for each protein and showed significant correlation with the presence of venous invasion (p = 0.0189), distant metastasis (p = 0.0073) and positive resection margins (p = 0.0067) (Table 2). Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion (p = 0.0062), N-stage (p = 0.0022) and PTB (p = 0.0041, Table 2). High peritumoral CD163-counts (CD163p) correlated with venous invasion (p = 0.0291), budding 10-in-10 (p = 0.0155), PTB (p = 0.0200) and ITB (p = 0.0253, Table 3). High intratumoral CD163-counts (CD163i) correlated significantly with T-stage (p = 0.006) and PTB (p = 0.0349, Table 3).

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