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Annals of Surgical Oncology 10:455-462 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Renal Cell Carcinoma Induces Prostaglandin E2 and T-Helper Type 2 Cytokine Production in Peripheral Blood Mononuclear Cells

Gordon P. Smyth, FRCSI, Philip P. Stapleton, PhD, Catherine B. Barden, MD, Juan R. Mestre, MD, Tracy A. Freeman, BA, Michael D. Duff, AFRCSI, Sirish Maddali, MD, Zhaoping Yan, MD and John M. Daly, MD, FACS

From the Department of Surgery, Weill Medical College of Cornell University/New York Presbyterian Hospital, New York, New York.

Correspondence: Address correspondence and reprint requests to: Philip P. Stapleton, PhD, Temple University School of Medicine, Departments of Surgery and Microbiology/Immunology, 3400 North Broad Street, Room 513 OMS, Philadelphia, PA 19140; Fax: 215-707-8820; E-mail: ppstap{at}temple.edu

Background: Patients with renal cell carcinoma (RCC) do not develop an effective antitumor immune response, despite significant infiltration by lymphocytes. Tumor production of immunosuppressive factors may account for this failure. The object of this study was to investigate the production of immunosuppressive mediators, especially prostaglandin E2 (PGE2), by RCC.

Methods: Peripheral blood mononuclear cells (PBMC) were cocultured with conditioned medium (CM) from human RCC cell lines in the presence or absence of NS-398, a selective cyclooxygenase 2 (COX-2) inhibitor. Supernatants were analyzed for levels of PGE2, interleukin (IL)-10, IL-6, IL-2, interferon-{gamma}, and IL-12. The effects of RCC CM on PBMC proliferation were also examined. The expression of basal and stimulated COX-2 messenger RNA in the cell lines was assessed by reverse transcriptase-polymerase chain reaction.

Results: RCC CM significantly increased PGE2 production by PBMC. T-helper type 2 (Th2) cytokine production was also significantly increased. Th1 cytokines were unchanged or decreased. RCC CM increased proliferation of PBMC. Coculture with NS-398 reduced PBMC PGE2 production to below control levels and significantly decreased IL-6 production and PBMC proliferation. NS-398 had no effect on cellular production of IL-10 or Th1 cytokines.

Conclusions: Human RCC inhibits the host antitumor immune response by promoting PGE2 production and Th2 cytokines in PBMC. Selective inhibition of COX-2 may have a role in abrogating this effect.

Key Words: Renal cell carcinoma • Prostaglandin E2 • Th2 cytokines • Peripheral blood mononuclear cells • COX-2 inhibition






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