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Cycloxygenase-2 Inhibition Augments the Efficacy of a Cancer Vaccine

Authors' Affiliation: Thoracic Oncology Research Laboratory, Philadelphia, Pennsylvania

Requests for reprints: Steven Albelda, Thoracic Oncology Research Laboratory, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160. Phone: 215-573-9933; Fax: 215-573-4469; E-mail: Albelda{at}mail.med.upenn.edu.

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-ß 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-, 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.

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