Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma.
OBJECTIVE
Regulatory T cells (Tregs) express the forkhead box transcription factor (FoxP3) and suppress the antitumor immune response. We investigated whether the intratumoral densities of FoxP3(+) and effector CD3(+) lymphocytes are associated with prognosis of patients with colon cancer.


METHODS
FoxP3 and CD3 expression and location were determined in stage II and III colon carcinomas (n = 160) and normal mucosa (n = 25) by immunohistochemistry; CD4 and FoxP3 were localized by dual immunofluorescence microscopy. T-cell markers were compared with pathological variables, DNA mismatch repair status, and patient survival using Cox proportional hazards models.


RESULTS
FoxP3(+) and CD3(+) T-cell densities were increased in carcinomas compared with autologous normal mucosa (P < .0001). An increase in intraepithelial FoxP3(+) cells was associated with poor tumor differentiation (P = .038), female sex (P = .028), and advanced patient age (P = .042). FoxP3(+) cell density was not prognostic, yet patients with tumors with reduced intraepithelial CD3(+) T-cell densities had reduced disease-free survival (DFS) rates (hazard ratio [HR], 1.87 [95% confidence interval, 1.10-3.16]; P = .018). A low intraepithelial CD3(+)/FoxP3(+) cell ratio predicted reduced DFS (46.2% vs 66.7% survival at 5 years; HR, 2.17 [95% confidence interval, 1.11-4.23]; P = .0205). The prognostic impact of these markers was maintained when tumors were stratified by mismatch repair status. By multivariate analysis, a low CD3(+)/FoxP3(+) cell ratio (P= .0318) and low numbers of CD3(+) T cells (P = .0397) predicted shorter DFS times and were stronger prognostic variables than tumor stage or number of lymph node metastases.


CONCLUSIONS
A low intraepithelial CD3(+)/FoxP3(+) cell ratio and reduced numbers of CD3(+) T cells were associated with shorter patient survival time, indicating the importance of an effector to Treg cell ratio in colon cancer prognosis.
Sinicrope
Frank A
FA
Miles and Shirley Fiterman Digestive Disease Center, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA. sinicrope.frank@mayo.edu
Rego
Rafaela L
RL
Ansell
Stephen M
SM
Knutson
Keith L
KL
Foster
Nathan R
NR
Sargent
Daniel J
DJ
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000367:Age Factors; D000368:Aged; D017252:CD3 Complex / Q000032:analysis*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008297:Male; D008856:Microscopy, Fluorescence; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome
D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors