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 IMCs in 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.
Highlights
Successful cancer vaccines need to stimulate a robust antitumor immune response, and need to alleviate the effects of immune-suppressive cell populations [1]
Immature myeloid cells are a heterogeneous population of myeloid precursor cells that are present in most cancers and which typically expand during disease progression [3]
We have recently shown that a therapeutic vaccine, consisting of a long TRP2-peptide co-delivered with α-GalCer in cationic liposomes, increased cytotoxic T-cell responses, and improved tumor survival in melanoma-bearing mice [24]
Summary
Successful cancer vaccines need to stimulate a robust antitumor immune response, and need to alleviate the effects of immune-suppressive cell populations [1]. Inflammatory factors secreted by tumor cells can polarize stromal and immune cells, including macrophages, immature myeloid cells (IMCs) [ known as myeloid-derived suppressor cells (MDSCs)], and T-cells, toward an immune-suppressive phenotype [2]. The constant secretion of inflammatory molecules by tumor cells into the systemic circulation promotes IMCs to egress from the bone marrow (BM) and to infiltrate the tumor where they suppress antitumor immunity [3]. Licofelone Improves Therapeutic Melanoma Vaccine been identified as one of the major pro-tumor immune populations and are positively correlated with melanoma progression, which makes them an attractive target for immunotherapy [4, 5]. Activated IMCs can themselves produce pro-inflammatory stimuli such as IL-6, prostaglandin E2 (PGE2), and VEGF, which provide a positive feedback loop for their recruitment and activation [8]
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