Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, Lisbon 1649-003, Portugal; Department of Pharmaceutics, The School of Pharmacy, University College London, 29/39 Brunswick Square, London WC1N 1AX, UK; School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, Lisbon 1649-003, Portugal; School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK.
Acta Biomater. 2018 Aug;76:193-207. doi: 10.1016/j.actbio.2018.06.029. Epub 2018 Jun 22.
α-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, simultaneously inducing an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model.
Combination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.
目的：α-半乳糖神经酰胺（GalCer）是一种广泛用于激活自然杀伤 T（NKT）细胞的糖脂，是一种有前途的癌症佐剂，包括黑色素瘤。然而，迄今为止，临床结果有限。本研究评估了 GalCer 与主要组织相容性复合体（MHC）I 类和 MHC II 类黑色素瘤相关肽抗原以及 Toll 样受体（TLR）配体 CpG 和单磷酰脂质 A（MPLA）之间的协同作用，我们打算通过纳米颗粒（NP）共递以来最大限度地发挥这些作用。这有望提高树突状细胞（DC）对 GalCer 的捕获，随后递呈给 NKT 细胞，同时诱导针对肿瘤的特异性 T 细胞介导的免疫。GalCer 与黑色素瘤肽和 TLR 配体的组合成功抑制了肿瘤生长。这些动物的肿瘤体积比未含 GalCer 的 NP 免疫小鼠的肿瘤体积低 5 倍。然而，当 GalCer 被包封或以其可溶性形式与抗原和 TLR 配体混合时，肿瘤生长得到了类似的控制。这两组均显示 T 淋巴细胞浸润肿瘤的程度增加，但只有载有 GalCer 的纳米疫苗诱导 NKT 和 NK 细胞的显著增强浸润。此外，这些动物的脾细胞分泌 IFN-γ 和 IL-4 的水平至少分别高出 1.5 倍和 2 倍，高于用溶液中的抗原和佐剂混合物处理的水平。总体而言，通过这种多价纳米疫苗联合递呈 NKT 激动剂与 TLR 配体和黑色素瘤抗原，在 B16F10 黑色素瘤小鼠模型中显示出协同的抗肿瘤免疫介导疗效。
