Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer.
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in the synthesis of prostaglandins. It is over-expressed in multiple cancers and has been associated with diminished tumor immunity. Dendritic cells (DCs) are considered candidates for cancer immunotherapy due to their ability to process and present antigens to T cells and stimulate immune responses. However, DC-based vaccines have exhibited minimal effectiveness against established tumors. In this study, we evaluated the effect of short-term administration of the selective COX-2 inhibitor celecoxib on the efficacy of DC-based vaccines in preventing and treating established 4T1 murine mammary tumors. We show that dietary celecoxib alone significantly suppresses the growth of primary tumors and the incidence of lung metastases in the prophylactic setting but is less effective against pre-established tumors. However, we demonstrate that celecoxib administered after primary tumor establishment synergizes with tumor lysate-pulsed DC and the adjuvant, GM-CSF, to improve the antitumor immune response by suppressing primary tumor growth and markedly reducing the occurrence of lung metastases. This triple combination therapy elicits a tumor-specific immune response evidenced by elevated IFN-gamma and IL-4 secretion by CD4+ T cells and results in increased infiltration of CD4+ and CD8+ T cells to the tumor site. In addition, dietary celecoxib inhibits angiogenesis evidenced by decreased vascular proliferation within the tumor and serum vascular endothelial growth factor levels. These studies suggest that short-term celecoxib therapy in combination with DC vaccines may be safely used for treating metastatic breast cancer.
Hahn
Tobias
T
Department of Microbiology and Immunology, University of Arizona, Tucson, AZ 85724, USA.
Alvarez
Irene
I
Kobie
James J
JJ
Ramanathapuram
Lalitha
L
Dial
Sharon
S
Fulton
Amy
A
Besselsen
David
D
Walker
Edwin
E
Akporiaye
Emmanuel T
ET
D000284:Administration, Oral; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D019496:Cancer Vaccines / Q000276:immunology*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D004334:Drug Administration Schedule; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D019496:Cancer Vaccines; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D011720:Pyrazoles; D013449:Sulfonamides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; D000068579:Celecoxib