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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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(A) Epithelial counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (B) Stromal counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (C) The ratio of epithelial-to-stromal FOXP3-positive cell counts in MSS and MSI-H colorectal cancers. Y axis was truncated at 0.4, § represents one extreme value at 0.7. Open circles represent outliers (above 1.5 interquartile ranges), * represent extreme values (above 3 interquartile ranges).
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fig2: (A) Epithelial counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (B) Stromal counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (C) The ratio of epithelial-to-stromal FOXP3-positive cell counts in MSS and MSI-H colorectal cancers. Y axis was truncated at 0.4, § represents one extreme value at 0.7. Open circles represent outliers (above 1.5 interquartile ranges), * represent extreme values (above 3 interquartile ranges).

Mentions: The comparison of MSI-H and MSS CRCs revealed a higher infiltration of MSI-H CRCs with FOXP3-positive cells. High-level microsatellite instability CRCs showed a trend towards a higher infiltration with FOXP3-positive cells in the tumour stroma (median: 181.5 cells per 0.25 mm2 in MSI-H vs 137.1 cells per 0.25 mm2 in MSS, P=0.06) and a significantly higher intraepithelial infiltration with FOXP3-positive Treg cells (median: 8.5 cells per 0.25 mm2 in MSI-H vs 3.1 cells per 0.25 mm2 in MSS, P<0.001). In addition, the ratio between intraepithelial and stromal FOXP3-positive cells was significantly higher in the MSI-H CRC group (0.05 in MSI-H vs 0.01 in MSS, P<0.001), indicating that in MSI-H CRC, a larger proportion of the FOXP3-positive cells was located in the epithelial compartment of the tumour. A graphical display of FOXP3-positive cell counts is shown in Figure 2. In accordance with previously published studies, we found higher numbers of intraepithelial CD3-positive T cells (median: 60.8 cells per 0.25 mm2 in MSI-H vs 14.1 cells per 0.25 mm2 in MSS, P<0.001) and CD8-positive T cells (median: 32.5 cells per 0.25 mm2 in MSI-H vs 6.3 cells per 0.25 mm2 in MSS, P<0.001) in MSI-H compared with MSS CRCs. In addition, the numbers of CD3-positive T cells (370.8 cells per 0.25 mm2 in MSI-H vs 320.1 cells per 0.25 mm2 in MSS, P=0.06) and CD8-positive cells (107.4 cells per 0.25 mm2 in MSI-H vs 47.2 cells per 0.25 mm2 in MSS P=0.009) infiltrating the tumour stroma were higher in MSI-H CRCs. The comparison of FOXP3-positive with CD8-positive cell counts revealed a positive correlation between the two markers (Spearman's rank correlation coefficient ρ=0.60, 95% confidence interval: 0.43–0.73).


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)

(A) Epithelial counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (B) Stromal counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (C) The ratio of epithelial-to-stromal FOXP3-positive cell counts in MSS and MSI-H colorectal cancers. Y axis was truncated at 0.4, § represents one extreme value at 0.7. Open circles represent outliers (above 1.5 interquartile ranges), * represent extreme values (above 3 interquartile ranges).
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getmorefigures.php?uid=PMC2600708&req=5

fig2: (A) Epithelial counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (B) Stromal counts of FOXP3-positive cells in MSS and MSI-H colorectal cancers. (C) The ratio of epithelial-to-stromal FOXP3-positive cell counts in MSS and MSI-H colorectal cancers. Y axis was truncated at 0.4, § represents one extreme value at 0.7. Open circles represent outliers (above 1.5 interquartile ranges), * represent extreme values (above 3 interquartile ranges).
Mentions: The comparison of MSI-H and MSS CRCs revealed a higher infiltration of MSI-H CRCs with FOXP3-positive cells. High-level microsatellite instability CRCs showed a trend towards a higher infiltration with FOXP3-positive cells in the tumour stroma (median: 181.5 cells per 0.25 mm2 in MSI-H vs 137.1 cells per 0.25 mm2 in MSS, P=0.06) and a significantly higher intraepithelial infiltration with FOXP3-positive Treg cells (median: 8.5 cells per 0.25 mm2 in MSI-H vs 3.1 cells per 0.25 mm2 in MSS, P<0.001). In addition, the ratio between intraepithelial and stromal FOXP3-positive cells was significantly higher in the MSI-H CRC group (0.05 in MSI-H vs 0.01 in MSS, P<0.001), indicating that in MSI-H CRC, a larger proportion of the FOXP3-positive cells was located in the epithelial compartment of the tumour. A graphical display of FOXP3-positive cell counts is shown in Figure 2. In accordance with previously published studies, we found higher numbers of intraepithelial CD3-positive T cells (median: 60.8 cells per 0.25 mm2 in MSI-H vs 14.1 cells per 0.25 mm2 in MSS, P<0.001) and CD8-positive T cells (median: 32.5 cells per 0.25 mm2 in MSI-H vs 6.3 cells per 0.25 mm2 in MSS, P<0.001) in MSI-H compared with MSS CRCs. In addition, the numbers of CD3-positive T cells (370.8 cells per 0.25 mm2 in MSI-H vs 320.1 cells per 0.25 mm2 in MSS, P=0.06) and CD8-positive cells (107.4 cells per 0.25 mm2 in MSI-H vs 47.2 cells per 0.25 mm2 in MSS P=0.009) infiltrating the tumour stroma were higher in MSI-H CRCs. The comparison of FOXP3-positive with CD8-positive cell counts revealed a positive correlation between the two markers (Spearman's rank correlation coefficient ρ=0.60, 95% confidence interval: 0.43–0.73).

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