Celecoxib up-regulates the expression of the ζ chain of T cell receptor complex in tumor-infiltrating lymphocytes in human cervical cancer

Purpose: We evaluated the effects of celecoxib treatment on tumor-infiltrating lymphocyte (TIL) subsets [CD3⁺, CD4⁺,CD8⁺, CD25⁺, and T cell receptor (TCR)-ζ-expressing cells] and tryptase-positive mast cells in cervical tumors. Circulating levels of cytokines [interleukin (IL)-1β, IL-10, tumor necrosis factor-α, 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-ζ chain after celecoxib treatment: indeed, in cases exposed to celecoxib, the percentage of TCR-ζ⁺ 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 ζ 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.