Original Article PGE2 contributes to TGF-beta induced T regulatory cell function in human non-small cell lung cancer
Felicita Baratelli, Jay M. Lee, Saswati Hazra, Ying Lin, Tonya C. Walser, Dorthe Schaue, Peter S. Pak, David Elashoff, Karen Reckamp, Ling Zhang, Michael C. Fishbein, Sherven Sharma, Steven M. Dubinett
UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Division of Cardiothoracic Surgery, Department of Surgery, Departments of Radiation Oncology, Biostatistics, and Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; Departments of Hematology and Medical Oncology, City of Hope, Duarte, CA; Molecular Medicine Laboratory, Veteran’s Affairs Greater Los Angeles Healthcare System, Los Angeles, CA.
Received June 23, 2010; accepted June 28, 2010, available online June 30, 2010
Abstract: CD4+CD25bright regulatory T cells (Treg) play an important role in cancer-mediated immunosuppression. We and others have previously shown that prostaglandin E2 (PGE2) and transforming growth factor beta (TGF-beta) induce CD4+CD25bright FOXP3+ Treg. Based on these studies, we investigated the requirement for PGE2 in Treg induction by TGF-beta. TGF-beta stimulation of human CD4+ T cells induced a COX-2-dependent production of PGE2. PGE2-neutralizing antibody treatment significantly reduced the suppressive function of TGF--induced Treg (TGF-beta-Treg) 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+CD25brightFOXP3+ 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 Treg activities. Interrupting TGF-beta and PGE2 signaling may be important in therapeutic interventions that aim to limit Treg function in lung cancer. (AJTR1006003).
Key words: T regulatory cells, PGE2, TGF-beta, non- small cell lung cancer, CD4+ T cells
Address all correspondence to: Jay M. Lee, MD Ronald Reagan UCLA Medical Center Section of Thoracic Surgery Division of Cardiothoracic Surgery Box 957313, Room 64-128 CHS10833 Le Conte Avenue, Los Angeles, CA 90095-7313 Tel: (310) 794-7333 FAX: (310) 794-7335 E-Mail: email@example.com