title: Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone.
abstract: Immune-suppressive cell populations impair antitumor immunity and can contribute to the failure of immune therapeutic approaches. We hypothesized that the non-steroidal anti-inflammatory drug licofelone, a dual cyclooxygenase-2/5-LO inhibitor, would improve therapeutic melanoma vaccination by reducing immune-suppressive cell populations. Therefore, licofelone was administered after tumor implantation, either alone or in combination with a peptide vaccine containing a long tyrosinase-related protein 2-peptide and the adjuvant α-galactosylceramide, all formulated into cationic liposomes. Mice immunized with the long-peptide vaccine and licofelone showed delayed tumor growth compared to mice given the vaccine alone. This protection was associated with a lower frequency of immature myeloid cells (IMCs) in the bone marrow (BM) and spleen of tumor-inoculated mice. When investigating the effect of licofelone on IMCsin vitro, we found that the prostaglandin E2-induced generation of IMCs was decreased in the presence of licofelone. Furthermore, pre-incubation of BM cells differentiated under IMC-inducing conditions with licofelone reduced the secretion of cytokines interleukin (IL)-10 and -6 upon lipopolysaccharides (LPS) stimulation as compared to untreated cells. Interestingly, licofelone increased IL-6 and IL-10 secretion when administered after the LPS stimulus, demonstrating an environment-dependent effect of licofelone. Our findings support the use of licofelone to reduce tumor-promoting cell populations.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Silke
authors.initials: S
authors.lastname: Neumann
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Shirley
authors.affiliation: Department of Microbiology and Immunology, University of Otago , Dunedin , New Zealand.
authors.forename: Roslyn A
authors.initials: RA
authors.lastname: Kemp
authors.affiliation: School of Pharmacy, University of Otago , Dunedin , New Zealand.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Hook
keywords: COX-2/5-LO; NSAID; cancer vaccine; immature myeloid cells; liposomes; melanoma; myeloid-derived suppressor cells; α-galactosylceramide