Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer.
BACKGROUND
Cyclooxygenase-2 (COX-2) is constitutively overexpressed in a variety of epithelial malignancies and is usually associated with a poor prognosis. COX-2-derived prostaglandin E2 transforms CD4+CD25+ T regulatory (Treg) cells (Tregs), and Tregs are thought to moderate the antitumor immune response. Herein, we investigated the prognostic value of tumor-infiltrating Treg cells and their correlation with COX-2 expression in resected non-small cell lung cancer (NSCLC).


METHODS
Intratumoral COX-2 and Treg expression were retrospectively assessed using immunohistochemistry in paraffin-embedded samples from 100 patients who had undergone complete resections for NSCLC. The expressions of COX-2 and Foxp3, which was most specific Treg cell marker, were compared with the clinicopathological variables, and the correlation between Foxp3+ Tregs and COX-2 expression was analyzed.


RESULTS
The recurrence-free survival (RFS) of patients with elevated COX-2 expression was significantly worse than that of patients without COX-2 expression. Tumor-infiltrating Foxp3-positive lymphocytes were positively correlated with COX-2 expression. The median count for Foxp3-positive lymphocytes was 3 (minimum-maximum, 0-24) in 10 high-power fields. The RFS of patients with tumors containing >or=3 Foxp3-positive cells (Foxp3 expression group) was significantly worse than that of patients with tumors containing <3 Foxp3-positive cells. In a multivariate analysis, only nodal status was an independent predictor of a significantly shorter RFS. However, in node-negative NSCLC, Foxp3 expression was an independent predictor of a significantly shorter RFS.


CONCLUSIONS
Tumor-infiltrating Foxp3+ Tregs were positively correlated with intratumoral COX-2 expression and were associated with a worse RFS, especially among patients with node-negative NSCLC.
Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kawasaki Medical School, Kurashiki, Japan. kshimizu@med.kawasaki-m.ac.jp
Katsuhiko
K
Shimizu
Masao
M
Nakata
Yuji
Y
Hirami
Takuro
T
Yukawa
Ai
A
Maeda
Kazuo
K
Tanemoto
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human