Neumann Silke, Shirley Simon A, Kemp Roslyn A, Hook Sarah M
School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
Front Immunol. 2016 Dec 5;7:537. doi: 10.3389/fimmu.2016.00537. eCollection 2016.
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 , we found that the prostaglandin E-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.
免疫抑制细胞群体损害抗肿瘤免疫，并可能导致免疫治疗方法的失败。我们假设，非甾体抗炎药利考非隆（一种双重环氧化酶-2/5-脂氧合酶抑制剂）将通过减少免疫抑制细胞群体来改善治疗性黑色素瘤疫苗接种。因此，在肿瘤植入后给予利考非隆，单独使用或与包含长酪氨酸酶相关蛋白2肽和佐剂α-半乳糖神经酰胺的肽疫苗联合使用，所有这些都配制成阳离子脂质体。与仅接种疫苗的小鼠相比，用长肽疫苗和利考非隆免疫的小鼠肿瘤生长延迟。这种保护作用与接种肿瘤的小鼠骨髓（BM）和脾脏中未成熟髓样细胞（IMC）的频率较低有关。在研究利考非隆对IMC的影响时，我们发现，在有利考非隆存在的情况下，前列腺素E诱导的IMC生成减少。此外，与未处理的细胞相比，在IMC诱导条件下分化的BM细胞与利考非隆预孵育后，脂多糖（LPS）刺激时细胞因子白细胞介素（IL）-10和-6的分泌减少。有趣的是，利考非隆在LPS刺激后给药时会增加IL-6和IL-10的分泌，这表明利考非隆具有环境依赖性作用。我们的研究结果支持使用利考非隆来减少促进肿瘤的细胞群体。
