Escribà-Garcia Laura, Alvarez-Fernández Carmen, Tellez-Gabriel Marta, Sierra Jorge, Briones Javier
Hematology Service, Hospital de la Santa Creu i Sant Pau, Mas Casanovas 90, 08041, Barcelona, Spain.
Laboratory of Experimental Hematology-IIB, Institut Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
J Transl Med. 2017 May 26;15(1):115. doi: 10.1186/s12967-017-1219-3.
Invariant natural killer T (iNKT) cells are a small population of lymphocytes with unique specificity for glycolipid antigens presented by non-polymorphic CD1d receptor on dendritic cells (DCs). iNKT cells play a central role in tumor immunology since they are implicated in the coordination of innate and adaptive immune responses. These cells can be activated with the prototypic lipid α-galactosylceramide (α-GalCer), stimulating interferon gamma (IFN-γ) production and cytokine secretion, which contribute to the enhancement of T cell activation.
We evaluated the antitumor effect of a combination of dendritic cells (DCs) and tumor cells with the iNKT cell agonist α-GalCer in a therapeutic model of B cell lymphoma. iNKT, NK and T cell phenotype was determined by flow cytometry. Serum cytokines were analyzed by Luminex technology. Significant differences between survival curves were assessed by the log-rank test. For all other data, Mann-Whitney test was used to analyze the differences between groups.
This vaccine induced a potent (100% survival), long-lasting and tumor-specific antitumor immune response, that was associated with an increase of both Th1 cytokines and IFN-γ secreting iNKT cells (4.59 ± 0.41% vs. 0.92 ± 0.12% in control group; p = 0.01) and T cells (CD4 IFN-γ: 3.75 ± 0.59% vs. 0.66 ± 0.18% p = 0.02; CD8 IFN-γ: 10.61 ± 0.84% vs. 0.47 ± 0.03% p = 0.002). Importantly, natural killer (NK) cells played a critical role in the antitumor effect observed after vaccination.
This study provides clinically relevant data for the development of iNKT-cell based immunotherapy treatments for patients with B cell malignancies.
不变自然杀伤T（iNKT）细胞是一小群淋巴细胞，对树突状细胞（DC）上非多态性CD1d受体呈递的糖脂抗原具有独特的特异性。iNKT细胞在肿瘤免疫学中发挥核心作用，因为它们参与先天和适应性免疫反应的协调。这些细胞可用原型脂质α-半乳糖神经酰胺（α-GalCer）激活，刺激干扰素γ（IFN-γ）产生和细胞因子分泌，这有助于增强T细胞活化。
我们在B细胞淋巴瘤治疗模型中评估了树突状细胞（DC）和肿瘤细胞与iNKT细胞激动剂α-GalCer联合使用的抗肿瘤效果。通过流式细胞术测定iNKT、NK和T细胞表型。采用Luminex技术分析血清细胞因子。通过对数秩检验评估生存曲线之间的显著差异。对于所有其他数据，使用Mann-Whitney检验分析组间差异。
这种疫苗诱导了强大的（100%存活）、持久的和肿瘤特异性的抗肿瘤免疫反应，这与Th1细胞因子和分泌IFN-γ的iNKT细胞（对照组为4.59±0.41% vs. 0.92±0.12%；p = 0.01）以及T细胞（CD4 IFN-γ：3.75±0.59% vs. 0.66±0.18%，p = 0.02；CD8 IFN-γ：10.61±0.84% vs. 0.47±0.03%，p = 0.002）的增加有关。重要的是，自然杀伤（NK）细胞在接种疫苗后观察到的抗肿瘤作用中起关键作用。
本研究为开发针对B细胞恶性肿瘤患者的基于iNKT细胞的免疫治疗提供了临床相关数据。
