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[Cancer Research 65, 5211-5220, June 15, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Tumor Cyclooxygenase-2/Prostaglandin E2–Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer

Sherven Sharma1,2,3, Seok-Chul Yang1,2,3, Li Zhu1,3, Karen Reckamp1,2,3, Brian Gardner1,2, Felicita Baratelli1,2, Min Huang1,2,3, Raj K. Batra1,2,3 and Steven M. Dubinett1,2,3

1 Department of Medicine, Lung Cancer Research Program and 2 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles and 3 Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

Requests for reprints: Steven M. Dubinett, Lung Cancer Research Program, David Geffen School of Medicine, University of California at Los Angeles, 37-131 Center for Health Sciences, 10833 LeConte Avenue, Los Angeles, CA 90095-1960. Phone: 310-794-6566; Fax: 310-267-2829; E-mail: sdubinett{at}mednet.ucla.edu.

Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non–small cell lung cancer. CD4+CD25+ T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4+CD25+ Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE2-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE2 to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.




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