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Celecoxib Up-Regulates the Expression of the Chain of T Cell Receptor Complex in Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Authors' Affiliations: ¹ Gynecologic Oncology Unit, Departments of ² Histology and ³ Pathology, Catholic University of Rome, Rome, and ⁴ Department of Oncology, Catholic University of Campobasso, Campobasso, Italy

Requests for reprints: Gabriella Ferrandina, Gynecologic Oncology Unit, Catholic University, L. go A. Gemelli 8, 00168 Rome, Italy. Phone: 39-6-3550-8736; Fax: 39-6-3550-8736; E-mail: gabriella.ferrandina{at}libero.it.

Purpose: We evaluated the effects of celecoxib treatment on tumor-infiltrating lymphocyte (TIL) subsets [CD3⁺, CD4⁺,CD8⁺, CD25⁺, and T cell receptor (TCR)-–expressing cells] and tryptase-positive mast cells in cervical tumors. Circulating levels of cytokines [interleukin (IL)-1ß, IL-10, tumor necrosis factor-, IL-6, and IL-12] and angiogenesis-modulating factors (vascular endothelial growth factor and endostatin) have also been analyzed.

Experimental Design: Cervical tumor biopsies and blood samples were obtained at the time of diagnosis and after 10 days of celecoxib treatment (400 mg b.i.d., at 8:00 a.m. and 8:00 p.m.) in 27 cases. Immunohistochemistry and ELISA assays were used to assess the expression of biological factors in tumor tissue and circulating levels of cytokines and angiogenic molecules.

Results: We showed a statistically significant increase in the percentage of TIL expressing the TCR- chain after celecoxib treatment: indeed, in cases exposed to celecoxib, the percentage of TCR-⁺ cells ranged from 5.0 to 50.0 (median, 22.5) with respect to baseline expression (range, 3.0-50.0; median, 10.0; P = 0.0016). There was no significant treatment-related difference in the percentage of CD3⁺, CD4⁺, CD8⁺, and CD25⁺ TIL as well as in tryptase-positive cells. IL-12 levels were significantly reduced in posttreatment samples with respect to baseline levels (P = 0.002). We also found a reduction in the circulating levels of vascular endothelial growth factor, and a statistically significant increase of serum endostatin levels (P = 0.035).

Conclusions: We reported the first evidence in humans that celecoxib restores expression by TIL in primary cervical tumors, suggesting that a positive modulation of immune function may serve as an additional mechanism supporting the antitumor effect of this class of drugs.