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Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas.

Yoon HH, Orrock JM, Foster NR, Sargent DJ, Smyrk TC, Sinicrope FA - PLoS ONE (2012)

Bottom Line: Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030).In contrast, FoxP3+ was not prognostic among CD8+(high) tumors.Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: T-lymphocyte infiltration into colon carcinomas can influence clinical outcome, and interactions among T cell subsets may be more informative than either subset alone. Our objective was to examine the prognostic impact of tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) in relation to cytotoxic CD8(+) T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials.

Methods: FoxP3(+) and CD8(+) densities in tumor epithelial and stromal compartments were analyzed by immunohistochemistry and quantified in resected, stage II and III colonic carcinomas (N = 216). Immune marker density was dichotomized at the median and categorized as high vs low. MMR status was classified as MMR deficient (dMMR) or proficient (pMMR). Cox models were adjusted for age, stage, and tumor grade.

Results: The density of FoxP3+ infiltration was similar in tumor stroma and epithelia, whereas CD8+ was higher in stroma. The prognostic impact of FoxP3+ and CD8+ T cell infiltration was stronger in stroma vs epithelia, and the density of each marker in stroma was independently associated with improved overall survival (OS). However, the impact of FoxP3+ on survival was dependent upon CD8+ density (P interaction = 040). Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030). In contrast, FoxP3+ was not prognostic among CD8+(high) tumors. FoxP3+ remained prognostic in CD8+(low) tumors after further adjustment for MMR or BRAF(V600E) mutation status. Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.

Conclusions: The prognostic impact of FoxP3+ and CD8+ T cell density are inter-dependent, whereby FoxP3+ exerts a favorable influence on survival only in colon cancers with low CD8+ infiltration.

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Patient survival and comparison of clinicopathologic variables by MMR status and T-cell density.Overall survival (OS) in deficient MMR (dMMR) vs proficient MMR (pMMR) colon carcinomas according to the density of FoxP3+ (a) or CD8+ (b) T lymphocytes in tumor stroma, showing similar OS among cases with dMMR vs pMMR with high densities of CD8+ or FoxP3+. Comparison of clinicopathological variables (c) between dMMR vs CD8+high or FoxP3+high pMMR cancers demonstrates differences in histologic grade and tumor site. Grade: 1 or 2, well- or moderately differentiated; 3 or 4, poor or undifferentiated.
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pone-0042274-g003: Patient survival and comparison of clinicopathologic variables by MMR status and T-cell density.Overall survival (OS) in deficient MMR (dMMR) vs proficient MMR (pMMR) colon carcinomas according to the density of FoxP3+ (a) or CD8+ (b) T lymphocytes in tumor stroma, showing similar OS among cases with dMMR vs pMMR with high densities of CD8+ or FoxP3+. Comparison of clinicopathological variables (c) between dMMR vs CD8+high or FoxP3+high pMMR cancers demonstrates differences in histologic grade and tumor site. Grade: 1 or 2, well- or moderately differentiated; 3 or 4, poor or undifferentiated.

Mentions: To remove potential confounding by dMMR, we determined the prognostic impact of the FoxP3+ and CD8+ in pMMR cases and found consistent results (Table 4). We sought to identify a favorable prognostic group using these immune markers within pMMR tumors. FoxP3+high or CD8+high cases that were pMMR showed similarly favorable OS as did 107 dMMR cases from the parent cohorts (Figure 3a–3b). Interestingly, pMMR cases with FoxP3+high or CD8+high showed differences in tumor site and histologic grade compared to phenotypic characteristics of dMMR cases [38] (Figure 3c).


Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas.

Yoon HH, Orrock JM, Foster NR, Sargent DJ, Smyrk TC, Sinicrope FA - PLoS ONE (2012)

Patient survival and comparison of clinicopathologic variables by MMR status and T-cell density.Overall survival (OS) in deficient MMR (dMMR) vs proficient MMR (pMMR) colon carcinomas according to the density of FoxP3+ (a) or CD8+ (b) T lymphocytes in tumor stroma, showing similar OS among cases with dMMR vs pMMR with high densities of CD8+ or FoxP3+. Comparison of clinicopathological variables (c) between dMMR vs CD8+high or FoxP3+high pMMR cancers demonstrates differences in histologic grade and tumor site. Grade: 1 or 2, well- or moderately differentiated; 3 or 4, poor or undifferentiated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412852&req=5

pone-0042274-g003: Patient survival and comparison of clinicopathologic variables by MMR status and T-cell density.Overall survival (OS) in deficient MMR (dMMR) vs proficient MMR (pMMR) colon carcinomas according to the density of FoxP3+ (a) or CD8+ (b) T lymphocytes in tumor stroma, showing similar OS among cases with dMMR vs pMMR with high densities of CD8+ or FoxP3+. Comparison of clinicopathological variables (c) between dMMR vs CD8+high or FoxP3+high pMMR cancers demonstrates differences in histologic grade and tumor site. Grade: 1 or 2, well- or moderately differentiated; 3 or 4, poor or undifferentiated.
Mentions: To remove potential confounding by dMMR, we determined the prognostic impact of the FoxP3+ and CD8+ in pMMR cases and found consistent results (Table 4). We sought to identify a favorable prognostic group using these immune markers within pMMR tumors. FoxP3+high or CD8+high cases that were pMMR showed similarly favorable OS as did 107 dMMR cases from the parent cohorts (Figure 3a–3b). Interestingly, pMMR cases with FoxP3+high or CD8+high showed differences in tumor site and histologic grade compared to phenotypic characteristics of dMMR cases [38] (Figure 3c).

Bottom Line: Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030).In contrast, FoxP3+ was not prognostic among CD8+(high) tumors.Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT

Background: T-lymphocyte infiltration into colon carcinomas can influence clinical outcome, and interactions among T cell subsets may be more informative than either subset alone. Our objective was to examine the prognostic impact of tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) in relation to cytotoxic CD8(+) T lymphocytes in patients with colon carcinomas characterized by DNA mismatch repair (MMR) status who participated in adjuvant chemotherapy trials.

Methods: FoxP3(+) and CD8(+) densities in tumor epithelial and stromal compartments were analyzed by immunohistochemistry and quantified in resected, stage II and III colonic carcinomas (N = 216). Immune marker density was dichotomized at the median and categorized as high vs low. MMR status was classified as MMR deficient (dMMR) or proficient (pMMR). Cox models were adjusted for age, stage, and tumor grade.

Results: The density of FoxP3+ infiltration was similar in tumor stroma and epithelia, whereas CD8+ was higher in stroma. The prognostic impact of FoxP3+ and CD8+ T cell infiltration was stronger in stroma vs epithelia, and the density of each marker in stroma was independently associated with improved overall survival (OS). However, the impact of FoxP3+ on survival was dependent upon CD8+ density (P interaction = 040). Among CD8+(low) tumors, FoxP3+(high) cases had significantly improved OS compared to FoxP3+(low) cases after adjustment for covariates (hazard ratio 0.43; 95% confidence interval 0.19 to 0.95; P = .030). In contrast, FoxP3+ was not prognostic among CD8+(high) tumors. FoxP3+ remained prognostic in CD8+(low) tumors after further adjustment for MMR or BRAF(V600E) mutation status. Additionally, these immune markers identified a pMMR subgroup with a similarly favorable OS as for dMMR tumors.

Conclusions: The prognostic impact of FoxP3+ and CD8+ T cell density are inter-dependent, whereby FoxP3+ exerts a favorable influence on survival only in colon cancers with low CD8+ infiltration.

Show MeSH
Related in: MedlinePlus