Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
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DOI：
10.3390/cancers12030661
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发表时间：
2020-03-01
期刊：
影响因子：
5.2
通讯作者：
Moretta, Lorenzo
中科院分区：
文献类型：
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作者：
Di Pace, Anna Laura;Tumino, Nicola;Moretta, Lorenzo
尽管自然杀伤(NK)细胞在肿瘤防御中起着关键作用，但由于其到达肿瘤部位的能力降低以及肿瘤微环境(TME)对其功能的抑制作用，其在癌症治疗中的应用仍然受到限制。在这项研究中，我们对IL2或IL15培养的人NK细胞的外切体进行了鉴定。两种细胞因子诱导的外切体数量相当，具有相似的货物成分。通过分析外切体表面包含或暴露的分子，可以鉴定出在NK细胞功能中发挥重要作用的分子，包括干扰素-γ、淋巴细胞功能相关抗原(LFA-1)、DNAX辅助分子-1(DNAM1)和程序性细胞死亡蛋白(PD-1)。重要的是，我们通过使用DNAM1或DNAM1配体的封闭抗体的实验揭示了DNAM1参与了外切体介导的细胞毒作用。此外，抗体介导的抑制外切体细胞毒作用可延缓靶细胞的凋亡。我们还提供了NK-exosome在短时间间隔后甚至在低浓度下发挥其细胞溶解活性的证据。关于它们在免疫治疗中的可能应用，NK外切体可以在外周血中检测到，它可以扩散到组织中，并在肿瘤部位发挥细胞溶解作用。这一特性为将癌症治疗与NK外切体相结合提供了线索。
Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-gamma, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes.