转4-1BBL基因的小鼠肝癌细胞疫苗抗肿瘤作用的研究
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摘要
机体对肿瘤的免疫主要靠细胞免疫，特别是T细胞免疫。而T细胞的激活除了MHC-抗原多肽复合物与T细胞受体(TCR)的结合所提供的第一信号外，共刺激分子(costimulatory molecules)提供的第二信号也起着至关重要的作用。目前发现的共刺激分子有B7、4-1BBL、CD40L及ICAM-1等，缺乏这些共刺激分子将导致T细胞进入克隆无能(clone angergy)或凋亡。因此，将共刺激分子导入肿瘤细胞以制备肿瘤疫苗成为近来肿瘤生物治疗的研究热点。
4-1BBL为新近发现的共刺激分子，结构上属肿瘤坏死因子超家族成员，其与4-1BB(为肿瘤坏死因子受体超家族成员)共同组成配体/受体对，研究表明，4-1BBL与其受体的结合可以调节多种免疫细胞的功能，可以有力的共刺激T细胞，使其增殖，增加它们的溶细胞能力。因此，应用4-1BBL诱发机体的抗肿瘤T细胞反应有着美好的前景。为了研究4-1BBL在抗肝癌免疫中的应用价值，我们克隆了小鼠4-1BBLcDNA并将其导入小鼠肝癌细胞Hepa1-6中制成肿瘤疫苗，观察了该肿瘤疫苗在体内外的特异性抗肿瘤作用。
首先我们采用RT-PCR的方法检测了4-1BBL在淋巴细胞及多株肝癌细胞中的表达，结果发现在经PHA诱导活化的人外周血淋巴细胞以及小鼠的脾淋
第四军医大学鹰士学位论文
巳细胞均可检测到 41 BBL的表达，但是未经诱导的静止的淋巴细胞则不表
达 41 BBL；对五株肝癌细胞系及一株正常肝细胞系的检测中，发现只有
HePGZ可表达 41 BBL，其它细胞系均未检测到表达。
为了获得4lBBL的全长基因，我们首先根据GENEBANK中小鼠4lBBL
的基因序列，设计了用于克隆4lBBLCDNA的引物，实验中选用C57BL／6
小鼠的脾细胞作为总RNA的来源，并预先用植物血凝素进行刺激，结果表明，
采用 RT－PCR的方法从活化的小鼠脾淋巴细胞中成功地克隆到了 m41 BBL基
因，并经测序证实序列完全正确；所构建的真核表达质粒
PCDNA3·l（＋）－m41 BBL在 COS－7细胞中获得了高效表达。
利用基因转染技术将共刺激分子 4－IBBL基因导入小鼠肝癌细胞，经筛选
后以期获得稳定表达克隆，结果显示，G4 18筛选后的Hepal6－m4lBBL细胞
能有效表达 m41 BBL，并且经提取基因组分析表明导入的基因己整合至基因
组中，而未转染的Hepal6细胞则未见m4lBBL的表达。体外增殖实验显
示转染后的细胞其生长速度，克隆形成能力等方面均不受影响，并且能持续
表达所导人的基因，说明外源基因导入后对野生瘤原有的生物学特性改变不
大。同系小鼠体内成瘤实验显示，与野生瘤相比，导入 41 BBL后皮下接种
的HePal6－m4lBBL细胞成瘤率显著降低，潜伏期延长，成瘤所需的起始细
胞数增加，成瘤后其生长速度减慢。
为了观察转染m4lBBL的小鼠Hepal6细胞是否具有诱导特异性抗肿瘤
免疫反应能力，我们采用了合适剂量的丝裂霉素C处理肿瘤细胞制备所需的
的肿瘤疫苗。然后观察了该肿瘤疫苗体外诱导CTL杀伤活性及刺激脾细胞产
生细胞囚于的作用，结果显示转 41 BBL的肝癌细胞疫苗能够诱导有效的针
对野生瘤的CTL杀伤效应，而对其它来源的肿瘤无效。将该肿瘤疫苗体外与
脾淋巴细胞共培养，其刺激脾细胞产生的IL2，TNF a及GM－CSF水平明显
上升。
应用上述肿瘤细胞疫苗观察了其对同系小鼠的兔疫保护和肿瘤模型的免
疫治疗作用，结果显示，应用 TCV－41 BBL免疫后，对亲本肝癌细胞有完全
的免疫保护作用，对接种的早期肿瘤模型，经 TCV－41 BBL治疗后可以使部
分小鼠保持无瘤生存，或者使肿瘤潜伏期延长、生长速度减慢。但对晚期模
型，其治疗效果不佳。
6
第四军医大学博士学位论文
综上所述，转 41 BBL的小鼠肝癌细胞疫苗，不论在体内还是体外，均
能够诱导有效的特异性抗肿瘤免疫应答，利用 4－IBBL进行免疫基因治疗，
为临床抗肿瘤应用研究提供了一个新的途径，继续研究其功能及其相关的调
节机制，或者设计更为合理有效安全的治疗方案将会为未来利用 41 BBL抗
肿瘤治疗开辟一片新的天地。
The immune responses to tumors are mostly dependent on the cell immunity, especially on T cell-mediated immunity. Successful T cell activation requires not only signals provided when antigen/MHC complex binds to the TCR, the other signals provided by costimulatory molecules are also important. Up to now many costimulatory molecules have been found, such as B7> 4-lBBLx CD40L and ICAM-1. The absence of these costimulatory molecules has been shown to lead to T cell anergy or apoptosis. Therefore, the introduction of costimulatory molecules into tumor cells to prepare tumor vaccine become to be a hotspot in the field of tumor biotherapeutic research in recent years.
4-IBB ligand (4-1 BBL) is a newly found costimulatory molecule. It is a member of the tumor necrosis factor (TNF) gene family that binds to 4-IBB, a T cell activation antigen which belongs to the TNF/nerve growth factor super family. The studies have demonstrated that the binding of 4-1 BBL with 4-IBB can
regulate the functions of several immune cells. 4-1BB-4-1BBL interactions can deliver a costimulatory signal for T cell activation and growth and promote the cell function of cytolysis. The powerful effects of 4-1BBL triggering on the T cell antitumor immune responses provide a novel strategy for increasing the potency of vaccines against tumors. To explore the prospects of the application of 4-1BBL in the anti-hepatocarcinoma immune response, we cloned a cDNA gene coding for the mouse costimulatory molecule 4-1BBL and further transfered it into murine hepatocellular carcinoma cell line Hepal-6. Then we observed the effects of this specific antitumor vaccine in vitro and in vivo.
Firstly, the expression of 4-1BBL in lymphocyte and several hepatocellular carcinoma cell lines were analyzed by RT-PCR. The results showed that 4-1BBL could be found in the human peripheral blood lymphocytes and murine splenocytes induced by PHA, but 4-1BBL could not be found in the quiescent and non-induced lymphocytes. Only one hepatocellular carcinoma cell line HepG2 could be detected the expression of 4-1BBL while the negative results were found in the other four hepatocellular carcinoma cell lines and one normal hepatic cell line.
To obtain the full gene sequence of 4-1BBL, we designed the primers of 4-1BBL according to the murine 4-1BBL gene sequence from GENEBANK. The total RNA was isolated from the murine splenocytes of C57BL/6 and the cells were induced by PHA before the abstraction of RNA. The m4-lBBL cDNA was obtained successfully by RT-PCR from the murine splenic lymphocytes. Sequencing analysis revealed that the amino acid sequence of m4-lBBL has no variation in nucleotide sequence as compared with the published sequence. The PCR product was cloned into pcDNA3.1(+) eukaryotic expression vector. This pCDNA3.1(+)- m4-lBBL vector was used to transfer the m4-lBBL gene into COS-7 cells, and the efficient expression was achieved.
We used the above vector to transfer the costimulatory molecule 4-1BBL gene into syngeneic murine hepatocellular carcinoma cell line Hepal-6. The clones with stable expression were obtained through G418 screening. The
Hepal-6-m4-lBBL cells efficiently expressed m4-lBBL after G418 selecting, and the exogenous gene was confirmed to have been integrated into chromosome of target cell. The gene of m4-lBBL didn't be detected in non-transfected Hepal-6 cells. The proliferation test in vitro showed that the growth rate and the ability in cloning of Hepal-6 cells weren't affected by the transfection, and they could express the m4-lBBL gene continuously. This demonstrated that the biological characters didn't be changed in wild-type tumor transfected with exogenous gene. The results of tumorigenicity experiment in syngeneic mice revealed that, as compared to wild-type tumor, mice subcutaneously injected with tumors expressing the vector Hepal-6-m4-lBBL developed fewer tumors and the latent period of tumor development was prolonged, the cell numbers for tumor development were increased and remarkable tumor growth inhibition was observed.
To
4-1BBL为新近发现的共刺激分子，结构上属肿瘤坏死因子超家族成员，其与4-1BB(为肿瘤坏死因子受体超家族成员)共同组成配体/受体对，研究表明，4-1BBL与其受体的结合可以调节多种免疫细胞的功能，可以有力的共刺激T细胞，使其增殖，增加它们的溶细胞能力。因此，应用4-1BBL诱发机体的抗肿瘤T细胞反应有着美好的前景。为了研究4-1BBL在抗肝癌免疫中的应用价值，我们克隆了小鼠4-1BBLcDNA并将其导入小鼠肝癌细胞Hepa1-6中制成肿瘤疫苗，观察了该肿瘤疫苗在体内外的特异性抗肿瘤作用。
首先我们采用RT-PCR的方法检测了4-1BBL在淋巴细胞及多株肝癌细胞中的表达，结果发现在经PHA诱导活化的人外周血淋巴细胞以及小鼠的脾淋
第四军医大学鹰士学位论文
巳细胞均可检测到 41 BBL的表达，但是未经诱导的静止的淋巴细胞则不表
达 41 BBL；对五株肝癌细胞系及一株正常肝细胞系的检测中，发现只有
HePGZ可表达 41 BBL，其它细胞系均未检测到表达。
为了获得4lBBL的全长基因，我们首先根据GENEBANK中小鼠4lBBL
的基因序列，设计了用于克隆4lBBLCDNA的引物，实验中选用C57BL／6
小鼠的脾细胞作为总RNA的来源，并预先用植物血凝素进行刺激，结果表明，
采用 RT－PCR的方法从活化的小鼠脾淋巴细胞中成功地克隆到了 m41 BBL基
因，并经测序证实序列完全正确；所构建的真核表达质粒
PCDNA3·l（＋）－m41 BBL在 COS－7细胞中获得了高效表达。
利用基因转染技术将共刺激分子 4－IBBL基因导入小鼠肝癌细胞，经筛选
后以期获得稳定表达克隆，结果显示，G4 18筛选后的Hepal6－m4lBBL细胞
能有效表达 m41 BBL，并且经提取基因组分析表明导入的基因己整合至基因
组中，而未转染的Hepal6细胞则未见m4lBBL的表达。体外增殖实验显
示转染后的细胞其生长速度，克隆形成能力等方面均不受影响，并且能持续
表达所导人的基因，说明外源基因导入后对野生瘤原有的生物学特性改变不
大。同系小鼠体内成瘤实验显示，与野生瘤相比，导入 41 BBL后皮下接种
的HePal6－m4lBBL细胞成瘤率显著降低，潜伏期延长，成瘤所需的起始细
胞数增加，成瘤后其生长速度减慢。
为了观察转染m4lBBL的小鼠Hepal6细胞是否具有诱导特异性抗肿瘤
免疫反应能力，我们采用了合适剂量的丝裂霉素C处理肿瘤细胞制备所需的
的肿瘤疫苗。然后观察了该肿瘤疫苗体外诱导CTL杀伤活性及刺激脾细胞产
生细胞囚于的作用，结果显示转 41 BBL的肝癌细胞疫苗能够诱导有效的针
对野生瘤的CTL杀伤效应，而对其它来源的肿瘤无效。将该肿瘤疫苗体外与
脾淋巴细胞共培养，其刺激脾细胞产生的IL2，TNF a及GM－CSF水平明显
上升。
应用上述肿瘤细胞疫苗观察了其对同系小鼠的兔疫保护和肿瘤模型的免
疫治疗作用，结果显示，应用 TCV－41 BBL免疫后，对亲本肝癌细胞有完全
的免疫保护作用，对接种的早期肿瘤模型，经 TCV－41 BBL治疗后可以使部
分小鼠保持无瘤生存，或者使肿瘤潜伏期延长、生长速度减慢。但对晚期模
型，其治疗效果不佳。
6
第四军医大学博士学位论文
综上所述，转 41 BBL的小鼠肝癌细胞疫苗，不论在体内还是体外，均
能够诱导有效的特异性抗肿瘤免疫应答，利用 4－IBBL进行免疫基因治疗，
为临床抗肿瘤应用研究提供了一个新的途径，继续研究其功能及其相关的调
节机制，或者设计更为合理有效安全的治疗方案将会为未来利用 41 BBL抗
肿瘤治疗开辟一片新的天地。
The immune responses to tumors are mostly dependent on the cell immunity, especially on T cell-mediated immunity. Successful T cell activation requires not only signals provided when antigen/MHC complex binds to the TCR, the other signals provided by costimulatory molecules are also important. Up to now many costimulatory molecules have been found, such as B7> 4-lBBLx CD40L and ICAM-1. The absence of these costimulatory molecules has been shown to lead to T cell anergy or apoptosis. Therefore, the introduction of costimulatory molecules into tumor cells to prepare tumor vaccine become to be a hotspot in the field of tumor biotherapeutic research in recent years.
4-IBB ligand (4-1 BBL) is a newly found costimulatory molecule. It is a member of the tumor necrosis factor (TNF) gene family that binds to 4-IBB, a T cell activation antigen which belongs to the TNF/nerve growth factor super family. The studies have demonstrated that the binding of 4-1 BBL with 4-IBB can
regulate the functions of several immune cells. 4-1BB-4-1BBL interactions can deliver a costimulatory signal for T cell activation and growth and promote the cell function of cytolysis. The powerful effects of 4-1BBL triggering on the T cell antitumor immune responses provide a novel strategy for increasing the potency of vaccines against tumors. To explore the prospects of the application of 4-1BBL in the anti-hepatocarcinoma immune response, we cloned a cDNA gene coding for the mouse costimulatory molecule 4-1BBL and further transfered it into murine hepatocellular carcinoma cell line Hepal-6. Then we observed the effects of this specific antitumor vaccine in vitro and in vivo.
Firstly, the expression of 4-1BBL in lymphocyte and several hepatocellular carcinoma cell lines were analyzed by RT-PCR. The results showed that 4-1BBL could be found in the human peripheral blood lymphocytes and murine splenocytes induced by PHA, but 4-1BBL could not be found in the quiescent and non-induced lymphocytes. Only one hepatocellular carcinoma cell line HepG2 could be detected the expression of 4-1BBL while the negative results were found in the other four hepatocellular carcinoma cell lines and one normal hepatic cell line.
To obtain the full gene sequence of 4-1BBL, we designed the primers of 4-1BBL according to the murine 4-1BBL gene sequence from GENEBANK. The total RNA was isolated from the murine splenocytes of C57BL/6 and the cells were induced by PHA before the abstraction of RNA. The m4-lBBL cDNA was obtained successfully by RT-PCR from the murine splenic lymphocytes. Sequencing analysis revealed that the amino acid sequence of m4-lBBL has no variation in nucleotide sequence as compared with the published sequence. The PCR product was cloned into pcDNA3.1(+) eukaryotic expression vector. This pCDNA3.1(+)- m4-lBBL vector was used to transfer the m4-lBBL gene into COS-7 cells, and the efficient expression was achieved.
We used the above vector to transfer the costimulatory molecule 4-1BBL gene into syngeneic murine hepatocellular carcinoma cell line Hepal-6. The clones with stable expression were obtained through G418 screening. The
Hepal-6-m4-lBBL cells efficiently expressed m4-lBBL after G418 selecting, and the exogenous gene was confirmed to have been integrated into chromosome of target cell. The gene of m4-lBBL didn't be detected in non-transfected Hepal-6 cells. The proliferation test in vitro showed that the growth rate and the ability in cloning of Hepal-6 cells weren't affected by the transfection, and they could express the m4-lBBL gene continuously. This demonstrated that the biological characters didn't be changed in wild-type tumor transfected with exogenous gene. The results of tumorigenicity experiment in syngeneic mice revealed that, as compared to wild-type tumor, mice subcutaneously injected with tumors expressing the vector Hepal-6-m4-lBBL developed fewer tumors and the latent period of tumor development was prolonged, the cell numbers for tumor development were increased and remarkable tumor growth inhibition was observed.
To
引文
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