MAGE-1/HSP70/MAGE-3融合蛋白肿瘤疫苗的构建及体内抑瘤效应的研究
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摘要
肿瘤疫苗正在成为肿瘤生物治疗的一种重要手段，越来越得到了人们广泛重视，研制开发疗效好、应用范围广的肿瘤疫苗已成为目前肿瘤防治研究的一个热点问题。肿瘤疫苗抗肿瘤作用的机理主要依赖于其中的肿瘤抗原，尤其是肿瘤特异性抗原发挥了重要作用。肿瘤抗原进入体内后通过抗原递呈激活机体免疫系统，诱导机体产生针对肿瘤的特异性细胞毒性T淋巴细胞(CTL)，进而杀伤肿瘤细胞。但是寻找特异性肿瘤抗原和使肿瘤抗原能够被有效地递呈，是肿瘤疫苗研制的关键问题，而且MHC的限制性和肿瘤异质性等问题使现有肿瘤疫苗的使用范围较小和／或效果不佳。热休克蛋白(Heat Shock Proteins, HSPs)是生物体(或离体培养的细胞)在不良环境因素作用下产生的具有高度保守性的应激蛋白，普遍存在于整个生物界。在细胞受到热、葡萄糖缺乏等应激条件下出现高效表达，正常情况下，其参与蛋白质的转位，折叠与装配以及在抗原的加工递呈过程中起着重要作用，因此HSP也被称为“分子伴侣”。研究表明，HSP可增强与其结合蛋白的抗原性。蛋白肿瘤疫苗能够被自身的免疫系统加工和递呈，从而消除了HLA的限制，可应用于不同的HLA病人，但缺少良好的肿
第四军医大学博士学位论文
瘤特异性抗原在很大程度上限制了蛋白疫苗的发展。MAGE抗原
的发现解决了这一难题，MAGE一1和MAGE一3是两种研究广泛的
肿瘤特异性抗原。MAGE的不同成员在不同组织类型肿瘤的表达
率相差很大，其中MAGE一1和MAGE一3的表达率相对较高。大多
数肿瘤中表达MAGE一1和/或MAGE一3，而在正常组织细胞(除胎
盘、辜丸外)均不表达。此外，有效地递呈肿瘤抗原，增强抗原
与APC的结合能力也是蛋白肿瘤疫苗必须要解决的问题。APC细
胞表面有HSP7O的受体，将肿瘤特异抗原与HSP70融合制备融合
蛋白肿瘤疫苗可望解决此问题，本研究构建以HSP70为疫苗载体，
MAGE一l和MAGE一3为靶抗原的肿瘤融合蛋白疫苗，研究其对小
鼠免疫系统的作用，及其对小鼠肿瘤模型的治疗作用。
1.采用免疫组化方法，我们利用用本室制备的MAGE一1的
兔多克隆抗体对MAGE一1在肿瘤组织、肿瘤细胞系及稳定转染细
胞MAGE一1表达情况进行了研究。研究发现，在肝细胞癌MAGE一1
的表达率为75%;胃癌为57%;结肠癌为60%，与文献报道相似。
MAGE一1的表达在上皮组织恶性肿瘤中明显高于间叶组织恶性肿
瘤中的表达(P<0.01)。与文献报道相符，MAGE一1在肝癌细胞系
7721、HHcc、HePGZ中均有表达，MAGE一1在星形细胞瘤细胞系
BT一325细胞、肾透明细胞癌细胞系786-0细胞、白血病细胞系HL60
细胞均不表达用于对照的正常组织(20例皮肤、胃肠道组织，脑
组织，肾组织等)均不表达MAGE一1。在49例恶性肿瘤中MAGE一1
表达与正常对照之间有显著差异(P<0.01)，其表达特点与文献报道
相同。
2.构建了MAGE一1与增强型绿色荧光蛋白(EGFP)基因共
表达的质粒PIREsZ一EGFP一MAGE一1，经测序，MAGE一1序列与
GeneBank公布的一致。通过脂质体用共表达质粒稳定转染B16细
胞，经荧光显微镜及免疫组化染色法检测，可见细胞内有EGFP
及MAGE一1的表达，成功的建立了可共表达MAGE一1与EGFP基
一4一
第四军医大学博士学位论文
因的B16细胞模型。在本实验中证实MAGE一1在转染MAGE一1的
B16中表达，而在转染MAGE一3的B16中得到阴性结果。
3 .HSP70/抗原肤肿瘤疫苗己得到广泛研究，肿瘤组织提取的
和基因工程生产的HSP70/抗原肤复合物最有可能含有多种肿瘤特
异的抗原肤，HSP70作为瘤苗免疫载体，激发机体产生抗肿瘤特
异的CTL，杀伤肿瘤细胞。基于此，本实验首先构建了MAGE一1、
MAGE一3、HSP70的原核表达载体pET28a(+)一MAGE一l、
PET28a(+)一MAGE一3、pET28城+)一HSp70，经测序无突变。转化大
肠杆菌DE3，IPTG诱导表达出了MAGE一l、MAGE一3、HSP70三
种蛋白，三种蛋白均为可溶性蛋白，经Ni一NTA Resin纯化得到了
4mg的MAGE一1蛋白(蛋白纯度为78%)、Zmg的MAGE一3蛋白(蛋
白纯度为86%)、lomg的HSP70蛋白(蛋白纯度为84%)，满
足了下一步的实验研究需要。
4.成功构建了MAGE一1、HSP70、MAGE一3的融合基因及其原
核表达载体pET28a(+)一MAGE一l一HSp70一MAoE一3，融合基因经测
序无突变，前段与MAGE一1中间280一573bP的片段一致，中间与
HsP70全长一致，后段与MAGE一3后段583一945饰的片段一致，
MAGE小MAGE一3一HsP70融合蛋白为不可溶蛋白，以包涵体形式
存在。经过包涵体的洗涤与纯化、包涵体经SM脉裂解、Ni一TA
R’e sin的变性纯化、梯度脉复性后2000mL的菌液中获得了包涵体
蛋白大约12omg(蛋白纯度为890/0)、其中3Omg复性融合蛋白经
ATP一garose4B柱活性鉴定与活性蛋白分离纯化。洗脱获得有生物
活性的MAGE一1一HsP70一MAGE一3复性融合蛋白7mg(蛋白纯度为
82%)，复性率为23.3%。
5.采用MAGE一1一HSP7O一MAGE一3融合蛋白疫苗免疫小鼠后，
分离脾淋巴细胞，采用取F一YELISPOT检测MAGE一l、MAGE一3
特异性T细胞数量，结果显示采用MAGE一1一HSP7O一MAGE一3融合
蛋白免疫的小鼠，其脾淋巴细胞中针对MAGE一1、MAGE一3的特
一5一
第四军医大学博士学位论文
异性T细胞
Tumor vaccine, as an important approach for tumor biological therapies, has being more and more attended, and exploring an efficient, broad-spectrum tumor vaccine has become a hotspot in the areas of tumor prevention and trerapy in recent years. Tumor antigen, especially the tumor specific antigen (TSA), which can generate tumor-specific cytotoxic T lymphocyte (CTL) and damage tumor cell, is the major mechanism of tumor vaccine. It is difficult to find a potential specific tumor antigen and make it presented efficiently in the design of tumor vaccine. Furthermore, the limitation of MHC and the polymorph of tumor cells are the major factors of the limited region and/or the low efficiency of tumor vaccine. Heat shock proteins (HSPs), a highly conserved protein in vivo (or isolating cells), participate in the folding, transport and assembling of proteins, so named "molecular chaperone". The expression of HSPs can be induced by the stresses such as heat and lack of glucose. On the other hand, HSPs play an import
ant role in the processing and presenting of
antigens, which could conjugate proteins or peptieds and improve their antigenicity. Tumor protein vaccine can be processed and presented by immune system, so it can be used in patients with different HLA without HLA limitation, but the deficiency of tumor specific antigen, in part, has limited the development of protein vaccine until MAGE antigen was found; Both MAGE-1 and MAGE-3 are widely studied. The expressions of MAGE family proteins deviate in different tumors, and MAGE-1 and MAGE-3 are two of most common tumor antigens, which express in most tumors respectively or jointly but not in normal tissues except the testes and placenta. Moreover, to facilitate APC uptake tumor vaccines and improve the presentation is still needed. In this research, we used HSP70 as the vaccine carrier and MAGE-1 and MAGE-3 as the targeting antigens to construct a fusion protein vaccine, and determine its humoral and cellular immune responses and the antitumor effects.
1. The MAGE-1 expressions in tumor tissues, cell lines and stable transfected cells were measured by the method of immunohistochemistry with anti-MAGE-1 serum. The results showed that the expression rates in hepatocellular carcinoma, gastric carcinoma and colon carcinoma were 75%, 57% and 60% respectively. The expressions of MAGE-1 in tumor tissues (n=49) were distinctly higher than the expressions in normal tissues (P<0.01), which was identical with that reported. In addition, the immunohistochemical detection also indicated that the expression of MAGE-1 was higher in discrete carcinomas than in sarcomas (P<0.01). The study demonstrated MAGE-1 expressed in hepatocellular carcinoma cell line (7721, HHCC, HepG2) and renal clear cell carcinoma cell line (786-o), but not astrocytoma cell line (BT-325) and leukemia cell line
(HL60). This character was similar to the MAGE-1 expression pattern in tumor tissues, so the same reason may account for it.
2. The eukaryotic expression plasmid pIRES2-EGFP-MAGE-l was constructed, and the sequence was identical with that reported in GeneBank. The plasmid was introduced into the mouse melanoma cell B16, and the EGFP was detected by fluorescent microscope and the expression of MAGE-1 was measured by the method of immunohistochemistry. The stable EGFP-MAGE-1 expression B16 cell line was constructed. In this study, we proved that MAGE-1 was expressed in the B16 cells transfected with MAGE-1 (B16-MAGE-1), but not in B16 cells transfected MAGE-3 (B16-MAGE-3).
3. HSP70-peptide complex whether isolated from tumor tissues or constructed by gene engineering are mostly likely to contain several tumor special antigenic peptide, and HSP70 was used as rumor vaccine carrier to generate tumor special CTL in vivo, and kill tumor cells. In this study we constructed prokaryotic expression plasmids of pET28a (+) -MAGE-1, pET28a (+) -MAGE-3 and pET28a (+) -HSP70, and no mutations were found after sequencing. MAGE-1, MAGE-3 and HSP70 proteins were expressed in t
第四军医大学博士学位论文
瘤特异性抗原在很大程度上限制了蛋白疫苗的发展。MAGE抗原
的发现解决了这一难题，MAGE一1和MAGE一3是两种研究广泛的
肿瘤特异性抗原。MAGE的不同成员在不同组织类型肿瘤的表达
率相差很大，其中MAGE一1和MAGE一3的表达率相对较高。大多
数肿瘤中表达MAGE一1和/或MAGE一3，而在正常组织细胞(除胎
盘、辜丸外)均不表达。此外，有效地递呈肿瘤抗原，增强抗原
与APC的结合能力也是蛋白肿瘤疫苗必须要解决的问题。APC细
胞表面有HSP7O的受体，将肿瘤特异抗原与HSP70融合制备融合
蛋白肿瘤疫苗可望解决此问题，本研究构建以HSP70为疫苗载体，
MAGE一l和MAGE一3为靶抗原的肿瘤融合蛋白疫苗，研究其对小
鼠免疫系统的作用，及其对小鼠肿瘤模型的治疗作用。
1.采用免疫组化方法，我们利用用本室制备的MAGE一1的
兔多克隆抗体对MAGE一1在肿瘤组织、肿瘤细胞系及稳定转染细
胞MAGE一1表达情况进行了研究。研究发现，在肝细胞癌MAGE一1
的表达率为75%;胃癌为57%;结肠癌为60%，与文献报道相似。
MAGE一1的表达在上皮组织恶性肿瘤中明显高于间叶组织恶性肿
瘤中的表达(P<0.01)。与文献报道相符，MAGE一1在肝癌细胞系
7721、HHcc、HePGZ中均有表达，MAGE一1在星形细胞瘤细胞系
BT一325细胞、肾透明细胞癌细胞系786-0细胞、白血病细胞系HL60
细胞均不表达用于对照的正常组织(20例皮肤、胃肠道组织，脑
组织，肾组织等)均不表达MAGE一1。在49例恶性肿瘤中MAGE一1
表达与正常对照之间有显著差异(P<0.01)，其表达特点与文献报道
相同。
2.构建了MAGE一1与增强型绿色荧光蛋白(EGFP)基因共
表达的质粒PIREsZ一EGFP一MAGE一1，经测序，MAGE一1序列与
GeneBank公布的一致。通过脂质体用共表达质粒稳定转染B16细
胞，经荧光显微镜及免疫组化染色法检测，可见细胞内有EGFP
及MAGE一1的表达，成功的建立了可共表达MAGE一1与EGFP基
一4一
第四军医大学博士学位论文
因的B16细胞模型。在本实验中证实MAGE一1在转染MAGE一1的
B16中表达，而在转染MAGE一3的B16中得到阴性结果。
3 .HSP70/抗原肤肿瘤疫苗己得到广泛研究，肿瘤组织提取的
和基因工程生产的HSP70/抗原肤复合物最有可能含有多种肿瘤特
异的抗原肤，HSP70作为瘤苗免疫载体，激发机体产生抗肿瘤特
异的CTL，杀伤肿瘤细胞。基于此，本实验首先构建了MAGE一1、
MAGE一3、HSP70的原核表达载体pET28a(+)一MAGE一l、
PET28a(+)一MAGE一3、pET28城+)一HSp70，经测序无突变。转化大
肠杆菌DE3，IPTG诱导表达出了MAGE一l、MAGE一3、HSP70三
种蛋白，三种蛋白均为可溶性蛋白，经Ni一NTA Resin纯化得到了
4mg的MAGE一1蛋白(蛋白纯度为78%)、Zmg的MAGE一3蛋白(蛋
白纯度为86%)、lomg的HSP70蛋白(蛋白纯度为84%)，满
足了下一步的实验研究需要。
4.成功构建了MAGE一1、HSP70、MAGE一3的融合基因及其原
核表达载体pET28a(+)一MAGE一l一HSp70一MAoE一3，融合基因经测
序无突变，前段与MAGE一1中间280一573bP的片段一致，中间与
HsP70全长一致，后段与MAGE一3后段583一945饰的片段一致，
MAGE小MAGE一3一HsP70融合蛋白为不可溶蛋白，以包涵体形式
存在。经过包涵体的洗涤与纯化、包涵体经SM脉裂解、Ni一TA
R’e sin的变性纯化、梯度脉复性后2000mL的菌液中获得了包涵体
蛋白大约12omg(蛋白纯度为890/0)、其中3Omg复性融合蛋白经
ATP一garose4B柱活性鉴定与活性蛋白分离纯化。洗脱获得有生物
活性的MAGE一1一HsP70一MAGE一3复性融合蛋白7mg(蛋白纯度为
82%)，复性率为23.3%。
5.采用MAGE一1一HSP7O一MAGE一3融合蛋白疫苗免疫小鼠后，
分离脾淋巴细胞，采用取F一YELISPOT检测MAGE一l、MAGE一3
特异性T细胞数量，结果显示采用MAGE一1一HSP7O一MAGE一3融合
蛋白免疫的小鼠，其脾淋巴细胞中针对MAGE一1、MAGE一3的特
一5一
第四军医大学博士学位论文
异性T细胞
Tumor vaccine, as an important approach for tumor biological therapies, has being more and more attended, and exploring an efficient, broad-spectrum tumor vaccine has become a hotspot in the areas of tumor prevention and trerapy in recent years. Tumor antigen, especially the tumor specific antigen (TSA), which can generate tumor-specific cytotoxic T lymphocyte (CTL) and damage tumor cell, is the major mechanism of tumor vaccine. It is difficult to find a potential specific tumor antigen and make it presented efficiently in the design of tumor vaccine. Furthermore, the limitation of MHC and the polymorph of tumor cells are the major factors of the limited region and/or the low efficiency of tumor vaccine. Heat shock proteins (HSPs), a highly conserved protein in vivo (or isolating cells), participate in the folding, transport and assembling of proteins, so named "molecular chaperone". The expression of HSPs can be induced by the stresses such as heat and lack of glucose. On the other hand, HSPs play an import
ant role in the processing and presenting of
antigens, which could conjugate proteins or peptieds and improve their antigenicity. Tumor protein vaccine can be processed and presented by immune system, so it can be used in patients with different HLA without HLA limitation, but the deficiency of tumor specific antigen, in part, has limited the development of protein vaccine until MAGE antigen was found; Both MAGE-1 and MAGE-3 are widely studied. The expressions of MAGE family proteins deviate in different tumors, and MAGE-1 and MAGE-3 are two of most common tumor antigens, which express in most tumors respectively or jointly but not in normal tissues except the testes and placenta. Moreover, to facilitate APC uptake tumor vaccines and improve the presentation is still needed. In this research, we used HSP70 as the vaccine carrier and MAGE-1 and MAGE-3 as the targeting antigens to construct a fusion protein vaccine, and determine its humoral and cellular immune responses and the antitumor effects.
1. The MAGE-1 expressions in tumor tissues, cell lines and stable transfected cells were measured by the method of immunohistochemistry with anti-MAGE-1 serum. The results showed that the expression rates in hepatocellular carcinoma, gastric carcinoma and colon carcinoma were 75%, 57% and 60% respectively. The expressions of MAGE-1 in tumor tissues (n=49) were distinctly higher than the expressions in normal tissues (P<0.01), which was identical with that reported. In addition, the immunohistochemical detection also indicated that the expression of MAGE-1 was higher in discrete carcinomas than in sarcomas (P<0.01). The study demonstrated MAGE-1 expressed in hepatocellular carcinoma cell line (7721, HHCC, HepG2) and renal clear cell carcinoma cell line (786-o), but not astrocytoma cell line (BT-325) and leukemia cell line
(HL60). This character was similar to the MAGE-1 expression pattern in tumor tissues, so the same reason may account for it.
2. The eukaryotic expression plasmid pIRES2-EGFP-MAGE-l was constructed, and the sequence was identical with that reported in GeneBank. The plasmid was introduced into the mouse melanoma cell B16, and the EGFP was detected by fluorescent microscope and the expression of MAGE-1 was measured by the method of immunohistochemistry. The stable EGFP-MAGE-1 expression B16 cell line was constructed. In this study, we proved that MAGE-1 was expressed in the B16 cells transfected with MAGE-1 (B16-MAGE-1), but not in B16 cells transfected MAGE-3 (B16-MAGE-3).
3. HSP70-peptide complex whether isolated from tumor tissues or constructed by gene engineering are mostly likely to contain several tumor special antigenic peptide, and HSP70 was used as rumor vaccine carrier to generate tumor special CTL in vivo, and kill tumor cells. In this study we constructed prokaryotic expression plasmids of pET28a (+) -MAGE-1, pET28a (+) -MAGE-3 and pET28a (+) -HSP70, and no mutations were found after sequencing. MAGE-1, MAGE-3 and HSP70 proteins were expressed in t
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