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Reduced T-Cell and Dendritic Cell Function Is Related to Cyclooxygenase-2 Overexpression and Prostaglandin E₂ Secretion in Patients With Breast Cancer

From the Departments of Surgery (BAP, RJG), Biochemistry and Molecular Biology (GDB, LBP, JLH, SJG, PM), and Biostatistics (JLH), Mayo Clinic College of Medicine, Scottsdale, Arizona.

Correspondence: Address correspondence and reprint requests to: Pinku Mukherjee, PhD, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 13400 E. Shea Blvd., Scottsdale, AZ 85259; Fax: 480-301-7017; E-mail: mukherjee.pinku{at}mayo.edu

Background: In several neoplastic diseases, including breast cancer, immunosuppression correlates with disease stage, progression, and outcome. Thus, thorough analysis of immune parameters in breast cancer patients may be beneficial in designing effective anticancer immune-based therapies.

Methods: We investigated dendritic cell and T-cell function in breast cancer patients at various stages of the disease and in age-matched controls. We also evaluated cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE₂) levels within the tumor milieu and in the circulation.

Results: T cells from cancer patients showed decreased proliferation in response to CD3 antibody stimulation. Analysis of T-cell helper type 1 and 2 cytokines revealed reduced levels of interferon-, tumor necrosis factor-, interleukin (IL)-12, and IL-2 and increased levels of IL-10 and IL-4. Dendritic cells from these patients showed significantly reduced expression of co-stimulatory molecules (B7 and CD40) and demonstrated reduced phagocytic ability, reduced antigen presentation to T cells, and reduced ability to mature in response to lipopolysaccharide. Data revealed increased synthesis of PGE₂, an immune suppressor, along with increased expression of COX-2, a key regulator of PGE₂ synthesis.

Conclusions: COX-2–induced PGE₂ may contribute to immunosuppression and may directly block antitumor immunity while promoting tumor growth, providing us with the rationale for using COX-2 inhibition combined with immunotherapy.

Key Words: Cyclooxygenase-2 • Prostaglandin E₂ • Dendritic cells • T cells • Breast cancer

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