Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion.
Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion.
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DOI：
10.1007/s00262-016-1864-z
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Sondel PM
中科院分区：
文献类型：
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作者：
Wang W;Erbe AK;Alderson KA;Phillips E;Gallenberger M;Gan J;Campana D;Hank JA;Sondel PM
输注同种异体NK细胞是造血系统恶性肿瘤和实体瘤的潜在免疫疗法。人类NK细胞上的杀伤免疫球蛋白样受体（KIR）与肿瘤细胞上的KIR配体之间的相互作用影响NK功能的大小。为了获得足够数量的NK细胞用于输注，已经测试了几种方法。一种有效的方法使用来自K562人红白血病系的细胞，这些细胞已被转染以表达活化41 BB配体（41 BBL）和膜结合白细胞介素15（mbIL 15）;与这些细胞共培养刺激NK细胞扩增和活化。KIR对离体扩增的NK细胞的功能重要性尚未详细研究。我们研究了扩增的NK细胞和靶细胞之间的KIR/KIR-配体相互作用如何影响扩增的NK细胞的功能。在与K562-mbIL 15 - 41 BBL细胞共培养12天后，扩增的NK细胞保持抑制特异性和通过KIR/KIR-配体相互作用确定的先前体内许可状态。添加抗CD 20抗体（利妥昔单抗）诱导NK介导的抗体依赖性细胞毒性（ADCC），并增强对CD 20+靶细胞的杀伤。然而，由KIR/KIR-配体相互作用诱导的部分抑制持续存在。最后，我们发现NK细胞与转导以表达各种KIR-配体的刺激细胞的延长的共培养物修饰了扩增的NK细胞产物的抑制性和活化性KIR库。这些研究表明，许可的相互作用，已知发生在NK个体发育也影响NK细胞功能后，NK细胞体外扩增。这些发现可以帮助供体选择并指导特定NK细胞亚群的扩增以用于癌症的过继治疗。
Infusion of allogeneic NK cells is a potential immunotherapy for both hematopoietic malignancies and solid tumors. Interactions between killer immunoglobulin-like receptors (KIR) on human NK cells and KIR-ligands on tumor cells influence the magnitude of NK function. To obtain sufficient numbers of NK cells for infusion, several approaches have been tested. One potent method uses cells from the K562 human erythroleukemia line that have been transfected to express activating 41BB ligand (41BBL) and membrane-bound interleukin15 (mbIL15); co-culture with these cells stimulates NK cell expansion and activation. The functional importance of KIRs on ex vivo expanded NK cells has not been studied in detail. We investigated how KIR/KIR-ligand interactions between expanded NK cells and target cells affect the function of expanded NK cells. After a 12-day co-culture with K562-mbIL15-41BBL cells, expanded NK cells maintained inhibition specificity and prior in vivo licensing status determined by KIR/KIR-ligand interactions. Addition of an anti-CD20 antibody (rituximab) induced NK-mediated antibody dependent cellular cytotoxicity (ADCC) and augmented killing of CD20+ target cells. However, partial inhibition induced by KIR/KIR-ligand interactions persisted. Finally, we found that extended co-cultures of NK cells with stimulatory cells transduced to express various KIR-ligand modified both the inhibitory and activating KIR repertoires of the expanded NK cell product. These studies demonstrate that the licensing interactions known to occur during NK ontogeny also influence NK cell function following NK expansion ex vivo. These findings can help donor selection and guide expansion of specific NK cell subsets for adoptive therapy of cancer.