Fractalkine/CX3CR1在肿瘤细胞的表达及其在NK细胞依赖的免疫监视机制中的重要作用
摘要
肿瘤免疫是免疫学研究的重要方向。虽然围绕肿瘤细胞发生、发展已经提出了不少的机制，对于肿瘤细胞如何逃避免疫细胞，特别是T细胞、NK细胞的监视，也有不少的实验解释。但是到目前为止肿瘤免疫学的研究对于肿瘤的临床治疗仍然不能完全的理论指导，还需要更广泛的研究去揭示肿瘤发生的秘密，为肿瘤的消除提供足够的支持。
趋化因子是一群分子量不大的可溶性蛋白，是免疫系统的重要组成部分，在免疫细胞的迁移和归巢方面起关键作用。同其他免疫系统成员一样，肿瘤细胞对趋化因子的利用也是其逃避免疫系统监视，完成肿瘤扩散的一个有效的手段。Fractalkine是一种较晚发现的趋化因子，其独特的分子结构，双重的存在形式，使其成为趋化因子研究的一个重要分子。但是其在肿瘤细胞中的表达情况的研究还不是很充分，其是否是肿瘤逃避免疫监视的一个机制成为令人关心的课题。
我们的工作首先检测了多种肿瘤细胞系中趋化因子fractalkine和它的受体CX3CR1的表达情况。该部分的结果显示了该趋化因子在肿瘤细胞系中的广泛表达，表明该趋化因子在肿瘤发生重的重要作用。该部分的结果还显示不仅该趋化因子的表达十分广泛，它的受体的表达也比较的多。原始组织不表达该受体的，发生肿瘤后有可能获得该受体的表达；来源细胞表达CX3CR1的，肿瘤发生后更有可能保留该特性。这一发现可能暗示，CX3CR1／fractalkine在肿瘤的转移中可能扮演不能忽视的角色。在功能方面，我们发现了肿瘤的对NK细胞的敏感性可能和NK细胞表面表达的CX3CR1和肿瘤表面表达的fractalkine有关系，因为fractalkine既可以作为趋化因子招募活化NK细胞，又同时拥有黏附分子的功能。
为了充分的了解CX3CR1／fractalkine系统对于NK细胞杀伤肿瘤中的贡献，我们具体研究了这一对分子在K562细胞对NK细胞的杀伤敏感性方面的作用。我们的工作部分解释了K562细胞对NK细胞敏感的原因。为此我们设计了多个实验。首先，我们证实了K562不仅表达fractalkine，同时也表达ADAM10。这提示了我们K562不仅表达fractalkine，并且在它的条件培养基中还含有可以活化NK细胞的可溶性蛋白。接下来的杀伤实验证实了我们的推测。加入适当比例的条件培养基，培养体系中的NK细胞可以被活化，而更好的杀伤肿瘤细胞。我们还是发现可溶性的fractalkine对NK-92细胞也有相同的效果。以可溶性fractalkine预刺激过的NK-92的杀伤能力明显的增强。而用抗体阻断fractalkine／CX3CR1的相互作用则可以明显的保护K562细胞免受NK-92细胞的杀伤，降低K562细胞对NK细胞毒活性的敏感性。这些工作就部分的阐述了K562细胞表达的fractalkine所具有的生理学意义
要充分了解CX3CR1／fractalkine系统对于NK细胞杀伤肿瘤中的贡献，处理在天然表达这一分子的肿瘤细胞上做研究之外，还需要仔细比较只有fractalkine表达有差异的两个细胞系不同。为此我们构建了两个不同的HeLa细胞系。它们都导入了pcDNA3载体，它们的唯一差异在于FKN-HeLa在细胞表面重组表达fractalkine蛋白，而mock-HeLa只导入了pcDNA3的空载体。在这两个细胞系的基础上，通过体外的细胞刺激和细胞杀伤实验，我们比较全面地证实了膜表面的fractalkine对NK细胞的活化功能，包括细胞因子的分泌和细胞毒活性。这些结果证明了肿瘤细胞可以通过趋化因子的产生而直接的作用于NK细胞，并可以通过NK细胞的这两种能力影响整个免疫系统。
我们的这些工作第一次比较全面的了解了fractalkine／CX3CR1在肿瘤中的分布情况，并且具体研究了这一对分子在NK细胞杀伤某些肿瘤细胞中的作用。在这基础上，通过构建的两个细胞系，我们证实了肿瘤细胞表面的fractalkine可以直接的和NK细胞相互作用，对免疫系统做出深刻的影响。这些结果为揭示肿瘤逃逸中趋化因子扮演的角色，确定NK细胞在肿瘤免疫中的作用给出了很好的线索。当然，为了揭示这些秘密还需要进行进一步的体内实验以深化现阶段的工作，这将成为未来工作的一个重要的方向。
Many of the chemokine receptors are typically found on natural killer cells, including CX3CR1, the receptor for the chemokine fractalkine (FKN). These Chemokine receptors typically expressed on natural killer cells could be activated by ligands including the membrane chemokine fractalkine (mFKN).Fractalkine is a newly identified chemokine, the only member of cxxxc family, and also called as CX3C. we didn't know if fractalkine play a key role in cancer immunosurveillance.
Firstly, we checked if tumor cell lines express fractalkine and CX3CR1. We found most tumor cells express fractalkine. And some of them express CX3CR1 at the same time. These results showed the importance of fractalkine in the cancer formation.
Then we explored whether interactions between CX3CR1 and FKN are relevant for NK cell functions in cytotoxicity against tumor. FKN expression was examined by polymerase chain reaction and CX3CR1 expression on NK cells was analyzed by flow cytometry. NK cell cytotoxicity was examined by 4-hour ~(51)Cr release assay. FKN was expressed on a variety of tumor cell lines such as K562 cells, a NK sensitive cell lines. Around 90% of peripheral blood NK cells and almost all NK cell line, NK-92 cells, expressed CX3CR1. Anti-CX3CR1 antibody strongly neutralized the cytotoxicity of NK cells against K562 cells, and pretreatment of NK cells with recombinant soluble FKN improved the cytolytic function on tumor cells. This study demonstrates that interaction between CX3CR1 on NK cells and FKN on tumor cells is involved in natural cytotoxicity of NK cells against tumor.
Thirdly, we investigated the function of mFKN on NK cell activation for interferon-γproduction and cytotoxicity against tumors. HeLa cells were transfected with membrane human fractalkine (mhFKN)-expressing vector, and the transcription and surface expression of mhFKN in transfected HeLa cells were confirmed by an RT-PCR analysis and immunofluorescence assay, respectively. After co-culture of NK-92 cells with FKN-HeLa cells, the intracellular IFN-γin NK-92 cells significantly increased if compared to mock-HeLa cells. The concentration of IFN-γalso increased in the supernatant of NK-92 cells simulated with mhFKN-HeLa cells. More over, cytolysis activity of NK-92 cells against K562 target tumor cells was significantly enhanced at each effectontarget ratio in 4-hour ~(51)Cr-release assays if the NK-92 cells were pretreated with mhFKN-HeLa, indicating that membrane fractalkine may activate the NK cells in killing process. This study further confirms that membrane-expressed fractalkine plays a critical role in NK cell activation.
These experiments gave evidence of the participation of fractalkine in cancer formation. And these evidence told us the interaction of fractalkine/CX3CR1 could activate NK cells directly, which play an important role in innate immunity and important in regulation of adoptive immunity. These results showed the importance of fractalkine for regulation of immune system by tumor cells.
趋化因子是一群分子量不大的可溶性蛋白，是免疫系统的重要组成部分，在免疫细胞的迁移和归巢方面起关键作用。同其他免疫系统成员一样，肿瘤细胞对趋化因子的利用也是其逃避免疫系统监视，完成肿瘤扩散的一个有效的手段。Fractalkine是一种较晚发现的趋化因子，其独特的分子结构，双重的存在形式，使其成为趋化因子研究的一个重要分子。但是其在肿瘤细胞中的表达情况的研究还不是很充分，其是否是肿瘤逃避免疫监视的一个机制成为令人关心的课题。
我们的工作首先检测了多种肿瘤细胞系中趋化因子fractalkine和它的受体CX3CR1的表达情况。该部分的结果显示了该趋化因子在肿瘤细胞系中的广泛表达，表明该趋化因子在肿瘤发生重的重要作用。该部分的结果还显示不仅该趋化因子的表达十分广泛，它的受体的表达也比较的多。原始组织不表达该受体的，发生肿瘤后有可能获得该受体的表达；来源细胞表达CX3CR1的，肿瘤发生后更有可能保留该特性。这一发现可能暗示，CX3CR1／fractalkine在肿瘤的转移中可能扮演不能忽视的角色。在功能方面，我们发现了肿瘤的对NK细胞的敏感性可能和NK细胞表面表达的CX3CR1和肿瘤表面表达的fractalkine有关系，因为fractalkine既可以作为趋化因子招募活化NK细胞，又同时拥有黏附分子的功能。
为了充分的了解CX3CR1／fractalkine系统对于NK细胞杀伤肿瘤中的贡献，我们具体研究了这一对分子在K562细胞对NK细胞的杀伤敏感性方面的作用。我们的工作部分解释了K562细胞对NK细胞敏感的原因。为此我们设计了多个实验。首先，我们证实了K562不仅表达fractalkine，同时也表达ADAM10。这提示了我们K562不仅表达fractalkine，并且在它的条件培养基中还含有可以活化NK细胞的可溶性蛋白。接下来的杀伤实验证实了我们的推测。加入适当比例的条件培养基，培养体系中的NK细胞可以被活化，而更好的杀伤肿瘤细胞。我们还是发现可溶性的fractalkine对NK-92细胞也有相同的效果。以可溶性fractalkine预刺激过的NK-92的杀伤能力明显的增强。而用抗体阻断fractalkine／CX3CR1的相互作用则可以明显的保护K562细胞免受NK-92细胞的杀伤，降低K562细胞对NK细胞毒活性的敏感性。这些工作就部分的阐述了K562细胞表达的fractalkine所具有的生理学意义
要充分了解CX3CR1／fractalkine系统对于NK细胞杀伤肿瘤中的贡献，处理在天然表达这一分子的肿瘤细胞上做研究之外，还需要仔细比较只有fractalkine表达有差异的两个细胞系不同。为此我们构建了两个不同的HeLa细胞系。它们都导入了pcDNA3载体，它们的唯一差异在于FKN-HeLa在细胞表面重组表达fractalkine蛋白，而mock-HeLa只导入了pcDNA3的空载体。在这两个细胞系的基础上，通过体外的细胞刺激和细胞杀伤实验，我们比较全面地证实了膜表面的fractalkine对NK细胞的活化功能，包括细胞因子的分泌和细胞毒活性。这些结果证明了肿瘤细胞可以通过趋化因子的产生而直接的作用于NK细胞，并可以通过NK细胞的这两种能力影响整个免疫系统。
我们的这些工作第一次比较全面的了解了fractalkine／CX3CR1在肿瘤中的分布情况，并且具体研究了这一对分子在NK细胞杀伤某些肿瘤细胞中的作用。在这基础上，通过构建的两个细胞系，我们证实了肿瘤细胞表面的fractalkine可以直接的和NK细胞相互作用，对免疫系统做出深刻的影响。这些结果为揭示肿瘤逃逸中趋化因子扮演的角色，确定NK细胞在肿瘤免疫中的作用给出了很好的线索。当然，为了揭示这些秘密还需要进行进一步的体内实验以深化现阶段的工作，这将成为未来工作的一个重要的方向。
Many of the chemokine receptors are typically found on natural killer cells, including CX3CR1, the receptor for the chemokine fractalkine (FKN). These Chemokine receptors typically expressed on natural killer cells could be activated by ligands including the membrane chemokine fractalkine (mFKN).Fractalkine is a newly identified chemokine, the only member of cxxxc family, and also called as CX3C. we didn't know if fractalkine play a key role in cancer immunosurveillance.
Firstly, we checked if tumor cell lines express fractalkine and CX3CR1. We found most tumor cells express fractalkine. And some of them express CX3CR1 at the same time. These results showed the importance of fractalkine in the cancer formation.
Then we explored whether interactions between CX3CR1 and FKN are relevant for NK cell functions in cytotoxicity against tumor. FKN expression was examined by polymerase chain reaction and CX3CR1 expression on NK cells was analyzed by flow cytometry. NK cell cytotoxicity was examined by 4-hour ~(51)Cr release assay. FKN was expressed on a variety of tumor cell lines such as K562 cells, a NK sensitive cell lines. Around 90% of peripheral blood NK cells and almost all NK cell line, NK-92 cells, expressed CX3CR1. Anti-CX3CR1 antibody strongly neutralized the cytotoxicity of NK cells against K562 cells, and pretreatment of NK cells with recombinant soluble FKN improved the cytolytic function on tumor cells. This study demonstrates that interaction between CX3CR1 on NK cells and FKN on tumor cells is involved in natural cytotoxicity of NK cells against tumor.
Thirdly, we investigated the function of mFKN on NK cell activation for interferon-γproduction and cytotoxicity against tumors. HeLa cells were transfected with membrane human fractalkine (mhFKN)-expressing vector, and the transcription and surface expression of mhFKN in transfected HeLa cells were confirmed by an RT-PCR analysis and immunofluorescence assay, respectively. After co-culture of NK-92 cells with FKN-HeLa cells, the intracellular IFN-γin NK-92 cells significantly increased if compared to mock-HeLa cells. The concentration of IFN-γalso increased in the supernatant of NK-92 cells simulated with mhFKN-HeLa cells. More over, cytolysis activity of NK-92 cells against K562 target tumor cells was significantly enhanced at each effectontarget ratio in 4-hour ~(51)Cr-release assays if the NK-92 cells were pretreated with mhFKN-HeLa, indicating that membrane fractalkine may activate the NK cells in killing process. This study further confirms that membrane-expressed fractalkine plays a critical role in NK cell activation.
These experiments gave evidence of the participation of fractalkine in cancer formation. And these evidence told us the interaction of fractalkine/CX3CR1 could activate NK cells directly, which play an important role in innate immunity and important in regulation of adoptive immunity. These results showed the importance of fractalkine for regulation of immune system by tumor cells.
引文
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