Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine.
Tumor-derived cyclooxygenase-2 (COX-2) and its product, prostaglandin E2, exert strong immunoinhibitory effects that block dendritic cell function and CD4+ and CD8+ T-cell proliferation and function. We have shown previously that the addition of an oral COX-2 inhibitor to immunogene therapy using IFN-beta markedly augmented therapeutic efficacy in murine tumor models. In this study, we hypothesized that COX-2 inhibition might also augment an antitumor vaccination strategy. Mice bearing tumors derived from TC1 cells, a tumor line that expresses the human papillomavirus (HPV) E7 protein, were thus vaccinated with an adenoviral vector expressing HPV E7 protein (Ad.E7). This vaccine approach effectively generated E7-specific CD8+ cells and slowed the growth of small tumors but had little effect on large tumors. However, feeding mice with the COX-2 inhibitor, rofecoxib, restored the effectiveness of the vaccine against large tumors and prolonged survival. This effect was accompanied by a larger percentage of E7-specific CD8+ cells in the regional draining lymph nodes and a markedly increased number of tumor-infiltrating E7-specific CD8+ cells (as determined by flow cytometry) and total CD8+ T cells (as determined by immunohistochemical staining). Increased immunocyte trafficking was likely mediated by the generation of a Th1-type tumor microenvironment because COX-2 inhibition increased expression levels of mRNA for IFN-gamma, interleukin-12, IP-10, and MIG while lowering the expression of vascular endothelial growth factor within tumors. This study shows that the effectiveness of a cancer vaccine can be significantly improved by adding COX-2 inhibition.
Haas
Andrew R
AR
Thoracic Oncology Research Laboratory, Philadelphia, Pennsylvania 19104-6160, USA.
Sun
Jing
J
Vachani
Anil
A
Wallace
Africa F
AF
Silverberg
Michael
M
Kapoor
Veena
V
Albelda
Steven M
SM
D000284:Administration, Oral; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D018925:Chemokines / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D005434:Flow Cytometry; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009856:Oncogene Proteins, Viral / Q000276:immunology; D027383:Papillomaviridae / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013450:Sulfones / Q000008:administration & dosage*
D019496:Cancer Vaccines; D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D009856:Oncogene Proteins, Viral; D013450:Sulfones; C116926:rofecoxib