PGE(2) contributes to TGF-beta induced T regulatory cell function in human non-small cell lung cancer

CD4(+)CD25(bright) regulatory T cells (T(reg)) play an important role in cancer-mediated immunosuppression. We and others have previously shown that prostaglandin E2 (PGE(2)) and transforming growth factor beta (TGF-beta) induce CD4(+)CD25(bright)FOXP3(+)T(reg). Based on these studies, we investigated the requirement for PGE(2) in Treg induction by TGF-beta. TGF-beta stimulation of human CD4(+) T cells induced COX-2-dependent production of PGE(2). PGE(2)-neutralizing antibody treatment significantly reduced the suppressive function of TGF-beta-induced T(reg) (TGF-beta-T(reg)) in vitro. TGF-beta concentration measured in the plasma of non-small cell lung cancer (NSCLC) patients directly correlated with the frequency of circulating CD4(+)CD25(bright)FOXP3(+)T cells. Flow cytometry analysis showed increased FOXP3 expression in circulating CD4(+)CD25(+)HLA-DR- cells of lung cancer patients compared to control subjects. Immunohistochemical analysis revealed co-expression of TGF-beta, COX-2, and FOXP3 in serial sections from resected lung tumor tissues. All together these observations suggest interplay between TGF-beta and COX-2 in the induction of T(reg) activities. Interrupting TGF-beta and PGE(2) signaling may be important in therapeutic interventions that aim to limit T(reg)function in lung cancer.