Originally published as JCO Early Release 10.1200/JCO.2008.18.7229 on December 8 2008

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Tumor-Infiltrating FOXP3⁺ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

Paul Salama, Michael Phillips, Fabienne Grieu, Melinda Morris, Nik Zeps, David Joseph, Cameron Platell, Barry Iacopetta

From the School of Surgery and Biostatistics Unit, Cancer Trials, Western Australian Institute for Medical Research, University of Western Australia; Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands; and Colorectal Cancer Unit, St John of God Hospital, Subiaco, Australia

Corresponding author: Barry Iacopetta, PhD, School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia; e-mail: barry.iacopetta{at}uwa.edu.au

Purpose 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.

Patients and 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).

Conclusion 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.

published online ahead of print at www.jco.org on December 8, 2008.

Supported in part by a Russell Walter Gibbon Medical Research Award from the University of Western Australia and by a grant from the Colorectal Surgical Society of Australia and New Zealand Foundation (P.S.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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