Institute of Medical Immunology, Martin-Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Int J Mol Sci. 2021 Sep 23;22(19):10227. doi: 10.3390/ijms221910227.
Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.
自然杀伤 (NK) 细胞是先天免疫系统的成员，在排斥 HLA I 类阴性肿瘤细胞方面发挥着重要作用。因此，一种既能激活 NK 细胞又能激活适应性免疫系统细胞的治疗性疫苗，可能会诱导更全面的细胞反应，从而增加肿瘤的消除。树突状细胞 (DC) 能够激活和扩增 NK 细胞，尤其是当 DC 中的 NFκB 途径被激活时，从而导致细胞因子 IL-12 的分泌。另一种突出的 NK 细胞激活剂是 IL-15，它可以与 IL-15 受体α链 (IL-15Rα) 结合，被转呈给 NK 细胞。然而，单核细胞来源的 DC 既不分泌 IL-15，也不表达 IL-15Rα。因此，我们设计了一种由 IL-15 和 IL-15Rα 组成的嵌合蛋白。在 mRNA 电穿孔后，融合蛋白可在 DC 的表面检测到，并增加了 NFκB 激活、产生 IL-12 的 DC 激活 NK 细胞的潜力，在体外生成的来自健康供体的细胞的自体细胞培养系统中。这些数据表明，嵌合的 IL-15/IL-15Rα 分子可以由单核细胞来源的 DC 表达，被转运到细胞表面，并具有激活 NK 细胞的功能。这些数据代表了进一步改善基于 DC 的癌症细胞免疫疗法的另一种可能性的初步概念验证。
