Ghinnagow Reem, De Meester Julie, Cruz Luis Javier, Aspord Caroline, Corgnac Stéphanie, Macho-Fernandez Elodie, Soulard Daphnée, Fontaine Josette, Chaperot Laurence, Charles Julie, Soncin Fabrice, Mami-Chouaib Fathia, Plumas Joel, Faveeuw Christelle, Trottein François
Univ. Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
Centre National de la Recherche Scientifique, UMR 8204, F-59000 Lille, France.
Oncoimmunology. 2017 Aug 18;6(9):e1339855. doi: 10.1080/2162402X.2017.1339855. eCollection 2017.
Vaccines designed to abrogate the tolerance of tumor self-antigens and amplify cytotoxic CD8 T cells (CTLs) have promise for the treatment of cancer. Type I natural killer (NKT) cells have attracted considerable interest in the cancer therapy field. In the current study, we have exploited the unique ability of NKT cells to serve as T-helper cells to license dendritic cells (DCs) for cross priming with the aim to generate efficient CTL antitumor responses. To this end, we designed a nanoparticle-based vaccine to target cross-priming DCs via the Clec9a endocytic pathway. Our results showed for the first time that simultaneous co-delivery of the NKT agonist α-galactosylceramide and tumor self-antigens (Trp2 and gp100) to CD8α DCs promotes strong antitumor responses in prophylactic and therapeutic settings (advanced solid tumor model in the mouse). We attributed the vaccine's therapeutic effects to NKT cells (but not to T-helper lymphocytes) and CD8 T cells. Efficacy was correlated with an elevated ratio between tumor antigen-specific CD8 T cells and regulatory CD4 T lymphocytes within the tumor. The nanoparticle-based vaccine actively targeted human CLEC9A-expressing BDCA3 DCs - the equivalent of murine cross-priming CD8α DCs - and induced a strong expansion of effector memory tumor self-antigen (Melan -A)-specific CD8 T cells from peripheral blood mononuclear cells sourced from healthy donors and melanoma patients. Together, our result shed light on novel therapeutic approaches for controlling tumor development.
旨在消除肿瘤自身抗原耐受性并增强细胞毒性CD8 T细胞（CTL）的疫苗在癌症治疗方面具有前景。I型自然杀伤（NKT）细胞在癌症治疗领域引起了相当大的关注。在当前研究中，我们利用NKT细胞作为辅助性T细胞来许可树突状细胞（DC）进行交叉启动的独特能力，旨在产生有效的CTL抗肿瘤反应。为此，我们设计了一种基于纳米颗粒的疫苗，通过Clec9a内吞途径靶向交叉启动DC。我们的结果首次表明，将NKT激动剂α-半乳糖神经酰胺和肿瘤自身抗原（Trp2和gp100）同时共递送至CD8α DC，在预防性和治疗性环境（小鼠晚期实体瘤模型）中可促进强烈的抗肿瘤反应。我们将疫苗的治疗效果归因于NKT细胞（而非辅助性T淋巴细胞）和CD8 T细胞。疗效与肿瘤内肿瘤抗原特异性CD8 T细胞与调节性CD4 T淋巴细胞之间升高的比例相关。基于纳米颗粒的疫苗主动靶向表达人CLEC9A的BDCA3 DC（相当于小鼠交叉启动的CD8α DC），并诱导来自健康供体和黑色素瘤患者外周血单核细胞的效应记忆肿瘤自身抗原（Melan -A）特异性CD8 T细胞强烈扩增。总之，我们的结果为控制肿瘤发展的新型治疗方法提供了线索。
