Istituto Giannina Gaslini, Genoa, Italy.
PLoS One. 2009 Dec 4;4(12):e8132. doi: 10.1371/journal.pone.0008132.
Despite Natural Killer (NK) cells were originally defined as effectors of spontaneous cytotoxicity against tumors, extremely limited information is so far available in humans on their capability of killing cancer cells in an autologous setting.
METHODOLOGY/PRINCIPAL FINDINGS: We have established a series of primary melanoma cell lines from surgically resected specimens and here showed that human melanoma cells were highly susceptible to lysis by activated autologous NK cells. A variety of NK cell activating receptors were involved in killing: particularly, DNAM-1 and NKp46 were the most frequently involved. Since self HLA class I molecules normally play a protective role from NK cell-mediated attack, we analyzed HLA class I expression on melanomas in comparison to autologous lymphocytes. We found that melanoma cells presented specific allelic losses in 50% of the patients analyzed. In addition, CD107a degranulation assays applied to NK cells expressing a single inhibitory receptor, revealed that, even when expressed, specific HLA class I molecules are present on melanoma cell surface in amount often insufficient to inhibit NK cell cytotoxicity. Remarkably, upon activation, also the so called "unlicensed" NK cells, i.e. NK cells not expressing inhibitory receptor specific for self HLA class I molecules, acquired the capability of efficiently killing autologous melanoma cells, thus additionally contributing to the lysis by a mechanism independent of HLA class I expression on melanoma cells.
CONCLUSIONS/SIGNIFICANCE: We have investigated in details the mechanisms controlling the recognition and lysis of melanoma cells by autologous NK cells. In these autologous settings, we demonstrated an efficient in vitro killing upon NK cell activation by mechanisms that may be related or not to abnormalities of HLA class I expression on melanoma cells. These findings should be taken into account in the design of novel immunotherapy approaches against melanoma.
尽管自然杀伤 (NK) 细胞最初被定义为对肿瘤具有自发细胞毒性作用的效应细胞，但迄今为止，人类对其在自体环境中杀伤癌细胞的能力知之甚少。
方法/主要发现：我们从手术切除的标本中建立了一系列原发性黑色素瘤细胞系，并在此表明人类黑色素瘤细胞对激活的自体 NK 细胞的溶解非常敏感。多种 NK 细胞激活受体参与杀伤：特别是，DNAM-1 和 NKp46 是最常涉及的。由于自身 HLA 类 I 分子通常在 NK 细胞介导的攻击中发挥保护作用，我们分析了黑色素瘤中与自体淋巴细胞相比的 HLA 类 I 表达。我们发现，在分析的 50%患者中，黑色素瘤细胞呈现出特定的等位基因缺失。此外，应用于表达单个抑制性受体的 NK 细胞的 CD107a 脱颗粒测定法表明，即使表达，特定的 HLA 类 I 分子也存在于黑色素瘤细胞表面，其数量通常不足以抑制 NK 细胞的细胞毒性。值得注意的是，在激活后，即使是所谓的“无执照”NK 细胞，即不表达针对自身 HLA 类 I 分子的抑制性受体的 NK 细胞，也获得了有效杀伤自体黑色素瘤细胞的能力，从而通过独立于 HLA 类 I 表达的机制进一步有助于溶解。黑色素瘤细胞。
结论/意义：我们详细研究了控制自体 NK 细胞识别和溶解黑色素瘤细胞的机制。在这些自体环境中，我们在 NK 细胞激活后通过可能与或不与黑色素瘤细胞 HLA 类 I 表达异常相关的机制证明了有效的体外杀伤。这些发现应在针对黑色素瘤的新型免疫治疗方法的设计中考虑。
Zotero 插件
