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High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability.

Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, von Knebel Doeberitz M, Kloor M - Br. J. Cancer (2008)

Bottom Line: CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's rho=0.56 and 0.55, respectively).Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells.These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Partnership Unit (MMPU), Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg 69120, Germany.

ABSTRACT
High-level microsatellite instability (MSI-H) in colorectal cancer accounts for about 12% of colorectal cancers and is typically associated with a dense infiltration with cytotoxic CD8-positive lymphocytes. The role of regulatory T cells that may interfere with the host's antitumoural immune response in MSI-H colorectal cancers has not been analysed yet. Using an antibody directed against the regulatory T-cell marker transcription factor forkhead box P3 (FOXP3), regulatory T cells were examined in 70 colorectal cancers with known MSI status (MSI-H, n=37; microsatellite stable, n=33). In MSI-H colorectal cancers, we found a significantly higher intraepithelial infiltration with FOXP3-positive cells (median: 8.5 cells per 0.25 mm(2) vs 3.1 cells per 0.25 mm(2) in microsatellite stable, P<0.001), and a significantly elevated ratio of intraepithelial to stromal infiltration (0.05 vs 0.01 in microsatellite stable, P<0.001). CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's rho=0.56 and 0.55, respectively). Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells. These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

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Representative immunofluorescence stainings. Double stainings for CD8 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the left panel and centre panel, respectively. Double staining for CD3 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the right panel.
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fig3: Representative immunofluorescence stainings. Double stainings for CD8 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the left panel and centre panel, respectively. Double staining for CD3 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the right panel.

Mentions: Recent studies indicated that FOXP3 may be expressed transiently in CD8-positive effector T cells upon activation (Shevach, 2006; Baron et al, 2007). To further characterize the phenotype of FOXP3-positive cells detected in CRC lesions, immunofluorescence double staining was performed using antibodies specific for CD8/FOXP3, and CD3/FOXP3 as a control. Five CRC lesions showing high numbers of intraepithelial FOXP3 cells were selected for the analysis. Immunofluorescence stainings showed that all detectable FOXP3-positive cells were negative for CD8. In contrast, nuclear FOXP3 signals were regularly accompanied by membrane-bound CD3 staining. Exemplary images of immunofluorescence analysis are shown in Figure 3.


High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability.

Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, von Knebel Doeberitz M, Kloor M - Br. J. Cancer (2008)

Representative immunofluorescence stainings. Double stainings for CD8 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the left panel and centre panel, respectively. Double staining for CD3 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the right panel.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600708&req=5

fig3: Representative immunofluorescence stainings. Double stainings for CD8 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the left panel and centre panel, respectively. Double staining for CD3 (Alexa Fluor 488, green) and FOXP3 (Alexa Fluor 594, red) in the right panel.
Mentions: Recent studies indicated that FOXP3 may be expressed transiently in CD8-positive effector T cells upon activation (Shevach, 2006; Baron et al, 2007). To further characterize the phenotype of FOXP3-positive cells detected in CRC lesions, immunofluorescence double staining was performed using antibodies specific for CD8/FOXP3, and CD3/FOXP3 as a control. Five CRC lesions showing high numbers of intraepithelial FOXP3 cells were selected for the analysis. Immunofluorescence stainings showed that all detectable FOXP3-positive cells were negative for CD8. In contrast, nuclear FOXP3 signals were regularly accompanied by membrane-bound CD3 staining. Exemplary images of immunofluorescence analysis are shown in Figure 3.

Bottom Line: CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's rho=0.56 and 0.55, respectively).Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells.These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Partnership Unit (MMPU), Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg 69120, Germany.

ABSTRACT
High-level microsatellite instability (MSI-H) in colorectal cancer accounts for about 12% of colorectal cancers and is typically associated with a dense infiltration with cytotoxic CD8-positive lymphocytes. The role of regulatory T cells that may interfere with the host's antitumoural immune response in MSI-H colorectal cancers has not been analysed yet. Using an antibody directed against the regulatory T-cell marker transcription factor forkhead box P3 (FOXP3), regulatory T cells were examined in 70 colorectal cancers with known MSI status (MSI-H, n=37; microsatellite stable, n=33). In MSI-H colorectal cancers, we found a significantly higher intraepithelial infiltration with FOXP3-positive cells (median: 8.5 cells per 0.25 mm(2) vs 3.1 cells per 0.25 mm(2) in microsatellite stable, P<0.001), and a significantly elevated ratio of intraepithelial to stromal infiltration (0.05 vs 0.01 in microsatellite stable, P<0.001). CD8-positive cell counts were related positively to the number of FOXP3-positive cells (Spearman's rho=0.56 and 0.55, respectively). Our results show that the elevated number of CD8-positive lymphocytes found in MSI-H colorectal cancers is paralleled by an enhanced infiltration with CD8-negative FOXP3-positive cells. These data suggest that FOXP3-positive cells may play a role in the regulation of the immune response directed against MSI-H colorectal cancers at the primary tumour site.

Show MeSH
Related in: MedlinePlus