Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells.
Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells.
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缺氧引起的NK细胞细胞毒性对多发性骨髓瘤的损伤可以通过IL-2激活NK细胞来克服。
DOI：
10.1371/journal.pone.0064835
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wieten L
中科院分区：
文献类型：
--
作者：
Sarkar S;Germeraad WT;Rouschop KM;Steeghs EM;van Gelder M;Bos GM;Wieten L
多发性骨髓瘤（MM）是一种存在于骨髓（BM）中的不可治愈的浆细胞恶性肿瘤。我们的目标是开发同种异体自然杀伤（NK）细胞免疫治疗MM。由于BM含有缺氧区域，肿瘤环境可以是免疫抑制性的，我们假设缺氧抑制NK细胞抗MM反应。通过阴性选择从健康供体分离NK细胞，并使用流式细胞术在代表缺氧BM的氧水平下检查NK细胞功能和表型。另外，用IL-2活化NK细胞以增强缺氧下NK细胞的细胞毒性。缺氧以氧依赖性方式减少MM细胞系的NK细胞杀伤。低氧条件下，NK细胞保持其对靶细胞的脱粒反应能力，但脱粒NK细胞的百分比略有下降。NK细胞或MM细胞不需要适应缺氧，因此，在杀伤过程中的氧水平是至关重要的。缺氧不改变NK细胞配体（HLA-ABC、-E、云母/B和ULBP 1 -2）和受体（KIR、NKG 2A/C、DNAM-1、NCR和2B 4）的表面表达。然而，它确实降低了活化NKG 2D受体以及细胞内穿孔素和颗粒酶B的表达。通过IL-2预活化NK细胞消除了缺氧的不利影响并增加了NKG 2D表达。这强调了活化的NK细胞可以介导抗MM作用，即使在缺氧条件下。缺氧破坏了NK细胞对多发性骨髓瘤的杀伤潜力，这可以通过IL-2活化来恢复。我们的研究表明，对于基于NK细胞的免疫疗法的设计，有必要在缺氧条件下研究NK细胞和肿瘤细胞之间的生物学相互作用。
Multiple Myeloma (MM) is an incurable plasma cell malignancy residing within the bone marrow (BM). We aim to develop allogeneic Natural Killer (NK) cell immunotherapy for MM. As the BM contains hypoxic regions and the tumor environment can be immunosuppressive, we hypothesized that hypoxia inhibits NK cell anti-MM responses. NK cells were isolated from healthy donors by negative selection and NK cell function and phenotype were examined at oxygen levels representative of hypoxic BM using flowcytometry. Additionally, NK cells were activated with IL-2 to enhance NK cell cytotoxicity under hypoxia. Hypoxia reduced NK cell killing of MM cell lines in an oxygen dependent manner. Under hypoxia, NK cells maintained their ability to degranulate in response to target cells, though, the percentage of degranulating NK cells was slightly reduced. Adaptation of NK- or MM cells to hypoxia was not required, hence, the oxygen level during the killing process was critical. Hypoxia did not alter surface expression of NK cell ligands (HLA-ABC, -E, MICA/B and ULBP1-2) and receptors (KIR, NKG2A/C, DNAM-1, NCRs and 2B4). It did, however, decrease expression of the activating NKG2D receptor and of intracellular perforin and granzyme B. Pre-activation of NK cells by IL-2 abrogated the detrimental effects of hypoxia and increased NKG2D expression. This emphasized that activated NK cells can mediate anti-MM effects, even under hypoxic conditions. Hypoxia abolishes the killing potential of NK cells against multiple myeloma, which can be restored by IL-2 activation. Our study shows that for the design of NK cell-based immunotherapy it is necessary to study biological interactions between NK- and tumor cells also under hypoxic conditions.
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影响因子：
20.3
作者：
Benson, Don M., Jr.;Hofmeister, Craig C.;Farag, Sherif S.
通讯作者：
Farag, Sherif S.
DOI：
10.1158/1078-0432.ccr-11-1347
发表时间：
2011-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Parkhurst MR;Riley JP;Dudley ME;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
20.3
作者：
Carbone, E;Neri, P;Venuta, S
通讯作者：
Venuta, S
影响因子：
82.9
作者：
Helmlinger, G;Yuan, F;Jain, RK
通讯作者：
Jain, RK
影响因子：
6.4
作者：
LOEFFLER, DA;JUNEAU, PL;HEPPNER, GH
通讯作者：
HEPPNER, GH