AJTR Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Am J Translational Res 2010;2(4):356-367

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

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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