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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 according to CD8+ and FoxP3+ T-cell density.Overall survival (OS) in resected colon carcinomas with (a) high vs (b) low density of cytotoxic CD8+ T-cell infiltration in tumor stroma according to FoxP3+ T-cell density in tumor stroma (P for interaction  = .040). Hazard ratios (HR) are adjusted for age, stage, and tumor grade.
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pone-0042274-g002: Patient survival according to CD8+ and FoxP3+ T-cell density.Overall survival (OS) in resected colon carcinomas with (a) high vs (b) low density of cytotoxic CD8+ T-cell infiltration in tumor stroma according to FoxP3+ T-cell density in tumor stroma (P for interaction  = .040). Hazard ratios (HR) are adjusted for age, stage, and tumor grade.

Mentions: To determine whether the prognostic impact of FoxP3+ and CD8+ was inter-dependent, we tested for their interaction and found a significant relationship for OS (P for interaction  = .040; Padjusted  = .07). FoxP3+ density stratified by CD8+ revealed that, among CD8+high tumors, OS was similarly favorable among FoxP3+highvs FoxP3+low tumors (adjusted P = .91; Figure 2a; Table 4). Among CD8+low tumors, however, OS was significantly improved in FoxP3+highvs FoxP3+low cases (HR 0.43; 95% CI 0.19 to 0.95; P = .030; Figure 2b; Table 4). Notably, the 5-year survival rate in the CD8+lowFoxP3+high group (84% [95% CI 73–98]) was similar to that of CD8+high tumors, and was lowest in cases with low densities of both markers (53% [95% CI 41–70]) (Figure 2a and 2b). Importantly, the associations of FoxP3+ with OS, when stratified by CD8+, were similar after further adjustment for MMR status.


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 according to CD8+ and FoxP3+ T-cell density.Overall survival (OS) in resected colon carcinomas with (a) high vs (b) low density of cytotoxic CD8+ T-cell infiltration in tumor stroma according to FoxP3+ T-cell density in tumor stroma (P for interaction  = .040). Hazard ratios (HR) are adjusted for age, stage, and tumor grade.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412852&req=5

pone-0042274-g002: Patient survival according to CD8+ and FoxP3+ T-cell density.Overall survival (OS) in resected colon carcinomas with (a) high vs (b) low density of cytotoxic CD8+ T-cell infiltration in tumor stroma according to FoxP3+ T-cell density in tumor stroma (P for interaction  = .040). Hazard ratios (HR) are adjusted for age, stage, and tumor grade.
Mentions: To determine whether the prognostic impact of FoxP3+ and CD8+ was inter-dependent, we tested for their interaction and found a significant relationship for OS (P for interaction  = .040; Padjusted  = .07). FoxP3+ density stratified by CD8+ revealed that, among CD8+high tumors, OS was similarly favorable among FoxP3+highvs FoxP3+low tumors (adjusted P = .91; Figure 2a; Table 4). Among CD8+low tumors, however, OS was significantly improved in FoxP3+highvs FoxP3+low cases (HR 0.43; 95% CI 0.19 to 0.95; P = .030; Figure 2b; Table 4). Notably, the 5-year survival rate in the CD8+lowFoxP3+high group (84% [95% CI 73–98]) was similar to that of CD8+high tumors, and was lowest in cases with low densities of both markers (53% [95% CI 41–70]) (Figure 2a and 2b). Importantly, the associations of FoxP3+ with OS, when stratified by CD8+, were similar after further adjustment for MMR status.

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