Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.
OBJECTIVE
To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities.


METHODS
Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival.


RESULTS
FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001).


CONCLUSIONS
FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.
Salama
Paul
P
School of Surgery and Biostatistics Unit, Cancer Trials, Western Australian Institute for Medical Research, University of Western Australia, Australia.
Phillips
Michael
M
Grieu
Fabienne
F
Morris
Melinda
M
Zeps
Nik
N
Joseph
David
D
Platell
Cameron
C
Iacopetta
Barry
B
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens