B7-H3调节髓源性抑制细胞凋亡促进小鼠前列腺癌进展的实验研究
摘要
目的：本课题利用自行构建的B7-H3高表达的小鼠前列腺癌RM-1（RM-1-B7-H3）及对照细胞株（RM-1-mock），通过体内、体外实验分析B7-H3在小鼠前列腺癌进展中的免疫作用机制。
方法：检索小鼠B7H3的核苷酸序列，合成小鼠B7H3基因片段，转入目的载体，利用Gateway Technology构建B7H3基因高表达的质粒载体，脂质体转染获得稳定RM-1-B7-H3转基因细胞以及RM-1-mock为对照细胞。应用荧光显微镜下观察转染绿色荧光蛋白表达、RT-PCR检测mRNA表达的变化以及流式细胞仪技术检测分析，鉴定RM-1-B7-H3转基因细胞的效率及稳定性。在此基础上，体外实验比较分析RM-1-B7-H3转基因细胞以及RM-1-mock细胞增值能力；自C57BL/6小鼠皮下接种RM-1-B7-H3转基因细胞以及RM-1-mock细胞，观察体内成瘤情况；分离不同实验组荷瘤小鼠肿瘤组织及脾脏组织，流式分析技术检测各组间Gr-1+CD11b+MDSC表达水平，并以PI评估MDSC凋亡情况；离体实验中，自健康C57BL/6小鼠脾脏分离纯化Gr-1+CD11b+MDSC，并分别与RM-1-B7-H3转基因细胞以及RM-1-mock细胞混合培养，以PI表达情况分析B7-H3对MDSC凋亡的影响；为进一步确认B7-H3对MDSC的凋亡作用，本论文同时采用siRNA技术干预髓源性细胞株THP-1上B7-H3表达构建THP-1B7-H3low细胞以及THP-1-NC组，体外实验分析B7-H3缺失对髓源性细胞凋亡的影响。此外，本论文还在利用环磷酰胺抑制C57BL/6骨髓增殖的基础上，再次皮下移植接种RM-1-B7-H3转基因细胞以及RM-1-mock细胞，观察肿瘤生长情况，分析B7-H3发挥促瘤作用是否依赖于髓源性细胞。
结果：成功构建稳定表达、高效表达B7-H3的RM-1转基因细胞。体外实验RM-1-B7-H3转基因细胞以及RM-1-mock细胞在增殖能力方面两者并无统计学差异；然而，体内实验发现RM-1-B7-H3转基因细胞肿瘤生长显著高于RM-1-mock细胞。进一步研究发现，荷瘤RM-1-B7-H3的C57BL/6小鼠肿瘤组织及脾脏组织中Gr-1+CD11b+MDSC细胞数量显著高于RM-1-mock荷瘤小鼠；同时，本论文还发现RM-1-B7-H3荷瘤小鼠体内MDSC凋亡率显著低于RM-1-mock荷瘤小鼠。体外实验也证实RM-1-B7-H3细胞株与RM-1-mock细胞株相比，脾脏Gr-1+CD11b+MDSC凋亡率显著下降；人髓源性细胞株THP-1-B7-H3~(low)体外凋亡水平显著高于THP-1-B7-H3~(high)；上述结果提示B7-H3在抑制MDSC凋亡中发挥了重要作用。此外，环磷酰胺抑制骨髓造血后再次移植接种RM-1-B7-H3细胞株与RM-1-mock细胞株，构建前列腺癌荷瘤小鼠模型，两者之间的肿瘤生长差异并不存在，提示B7-H3促进前列腺癌生长依赖于髓源性细胞。
结论:众多研究均证实B7-H3高表达与前列腺癌进展密切相关，然而其中的作用机制并不清楚。本论文利用转基因技术构建B7-H3差异表达的RM-1细胞株，体内实验证实B7-H3可以促进小鼠前列腺癌细胞成瘤，其机制可能是B7-H3抑制髓源性抑制细胞凋亡，并通过聚集髓源性抑制细胞促进前列腺癌进展。
Objective: We regulated murine prostate cancer RM-1cells B7H3gene expressionusing gene transfection techniques. We observed mouse prostate cancer cell line of RM-1proliferation in the role of B7H3by in vivo and in vitro experiments, to explore its possiblemechanism.
Methods: We retrieved mice B7H3the nucleotide sequence, synthesized murineB7H3gene fragment, and transferred to the destination vector, using Gateway Technology.B7H3gene high expression plasmid vector was constructed. Transfected genes wereconsistent with the purpose of gene detected by gene sequencing. RT-PCR was used todetect mRNA expression before and after the plasmid construction. The above twomethods identified that the plasmids were successfully constructed. Prostate cancer in miceRM-1cells were stable transfection, and then transfected with plasmid vector B7H3geneRM-1cells as a control. Application observed by fluorescence microscopy transfected withgreen fluorescent protein expression to determine transfection success. After transfectionthe B7H3gene expression level was used to detect changes in mRNA expression byRT-PCR. The B7H3ene expression at the protein level changes in the two groups of cellswas detected by flow cytometry. Detection further confirmed that the B7H3gene wasstable transfection. In the part of in-vitro experiments,the RM-1cells were divided intotwo groups: the experimental group (B7-H3expression group) and negative control group(B7-H3low expression group only transfected with GFP). Cultured in vitro under the sameconditions, the murine prostate cancer cell changes were observated by counting thenumber of the cells. RM-1cell growth rate of the two groups were detected for comparingB7H3gene expression with low B7H3gene expression in mouse prostate cancer cellgrowth in vitro. Mice spleen was taken out and cut into pieces. The tissue was washed,then centrifuged into single cell suspension after grinding to obtain cell pellet. Add to Gr-1~+CD11b~+antibody on sorting by flow cytometry, MDSC was separated. Gr-1~+CD11b~+ cells from the spleen separation and purification were mixed culture with prostate cancerRM-1cells of the experimental group and the control group in vitro. The cells werecollected and detected by flow cytometry after cultured.We found the group of B7H3highexpression inhibit myeloid derived suppressor cell apoptosis in vitro. When THP-1cellsB7H3gene expression were lowered by small interfering RNA， marrow-derived myeloidTHP-1cell apoptosis were observed by flow cytometry. In the part of in vivoexperiments,high B7H3expression RM-1cells and low B7H3gene expression RM-1cellswere implanted in mice inguinal subcutaneous. Tumor growth was continuously observedafter implantion. The time of tumor formation and tumor size changes were recorded. Invivo testing to22days, experimental mice were sacrificed, and specimens were taken fromthe tumor and the spleen of experimental mice.The specimens were cut into smallpieces.After grinding and PBS fully washing blood cells and impurities, the specimenscentrifuged to obtain cell pellet. The cells were added to different antibodies on flowcytometry. B7H3gene expression and apoptosis were detected in transplanted tumor cellsand spleen cells. Myeloid derived suppressor cells expression and apoptosis were detected.Finally, cyclophosphamide was role in the spleen of experimental mice.to suppress bonemarrow lymphocytes. The size of the tumor volume changed by the B7H3gene expressionof experimental mice was observed without the interference of the bone marrow immunecells.
Results: The B7H3gene expression plasmid vector was successfully constructed.PCR amplification experiments confirmed that the the PCR identification bands around theplasmid construct theoretical size match the size of1200bp, with the purpose of Articlebelt. DNA sequencing showed that the nucleotide sequence of the insertion sites intoexperimental gene target gene fragment is entirely correct. The recombinant plasmidvectors by Gateway Technology B7H3gene were transducted into murine prostate cancerRM-1cells. The constructed plasmid B7H3support both at the mRNA level and at theprotein level could improve B7H3gene expression with the high transfection efficiency.After repeatedly subcultured the cells of the two experimental groups were extracted.Flowcytometry showed there are significant differences in the two groups of cells B7H3geneexpression. The experiment further confirmed that the B7H3gene was stable transfection.The in vitro cell growth rate results showed that the experimental group (B7-H3+group)and the negative control group RM-1cells were no significant difference. Purification Gr-1~+CD11b~+spleen cells were respectively mixed culture with RM-1prostate cancer cellsin mice of experimental group and control group. The cells were collected and detected byflow cytometry after cultured. B7-H3~+group, as compared to B7-H3-group, showedpreferentially inhibiting MDSC apoptosis. Marrow the endogenous THP-1cells apoptosisincidence rised after small interfering RNA reduced THP-1cells expression of humanB7H3. The two groups of mice prostate cancer cells were subcutaneously inoculated inmice groin. The tumorigenic time was recorded and tumor size were measured every twodays.There were significant differences in the two groups of tumor size. Tumors in miceappeared in B7H3gene high expression group earlier than the the B7H3genes lowexpression group.Tumor in experimental group grew faster than that in the controlgroup.The average tumor volume of experimental group increased significantly. Flowcytometry detected that the B7H3expression of mice transplanted tumor cells in B7H3gene regulation group was significantly increased. The in vivo experiments showed, theRM-1cells of B7H3gene regulation group in vivo tumorigenicity increased (P<0.01).After in Vivo cultured to22days, tumor-bearing mice were sacrificed by broken theneck. Specimens from tumor and spleen of experimental mice were extracted, recordingtumor volumes. Tumor cells and spleen cells were extracted from the two groups ofexperimental mice. The B7H3gene expression in tumor cells in mice inguinalsubcutaneous were detected by flow cytometry.That was also recorded including cellproliferation and apoptosis of myeloid derived suppressor cell proliferation and prostatecancer tumors in mice. The B7H3gene expression weakened after in vivo cultivation in thethe B7H3gene high expression group, but it was still higher than the B7H3gene lowexpression group.There was statistically significant difference between the two groups. Themyeloid derived suppressor cells of experimental group accelerated proliferation andapoptosis decreased while prostate cancer tumors in mice accelerated proliferation andapoptosis decreased. That was confirmed the B7H3gene in vivo promoted thedevelopment of tumors at the same time adjusted myeloid derived cells.The two groups ofexperimental mice were treated by Cyclophosphamide and then inoculated two groups ofprostate cancer cells RM-1in mice groin subcutaneous. There was no significant differencebetween the two groups of mice on transplanted tumor growth rate and size of tumor. Theexperiment proved B7H3promote tumor formation in vivo through the role of immunecells in the body.
Conclusions: The plasmid vector was constructed successfully，and B7H3gene wasstably transfected in RM-1cell line. That the stable transfection of B7H3gene expressionby plasmid-mediated was no obvious promotion RM-1cell apoptosis in vitro. But itinhibited RM-1cell growth; promoted the RM-1tumors in vivo tumorigenicity andprogress. B7H3gene stably transfected regulated MDSC to promote RM-1tumorprogression.The B7H3site is expected to become auxiliary potential target on gene therapyfor prostate cancer.
方法：检索小鼠B7H3的核苷酸序列，合成小鼠B7H3基因片段，转入目的载体，利用Gateway Technology构建B7H3基因高表达的质粒载体，脂质体转染获得稳定RM-1-B7-H3转基因细胞以及RM-1-mock为对照细胞。应用荧光显微镜下观察转染绿色荧光蛋白表达、RT-PCR检测mRNA表达的变化以及流式细胞仪技术检测分析，鉴定RM-1-B7-H3转基因细胞的效率及稳定性。在此基础上，体外实验比较分析RM-1-B7-H3转基因细胞以及RM-1-mock细胞增值能力；自C57BL/6小鼠皮下接种RM-1-B7-H3转基因细胞以及RM-1-mock细胞，观察体内成瘤情况；分离不同实验组荷瘤小鼠肿瘤组织及脾脏组织，流式分析技术检测各组间Gr-1+CD11b+MDSC表达水平，并以PI评估MDSC凋亡情况；离体实验中，自健康C57BL/6小鼠脾脏分离纯化Gr-1+CD11b+MDSC，并分别与RM-1-B7-H3转基因细胞以及RM-1-mock细胞混合培养，以PI表达情况分析B7-H3对MDSC凋亡的影响；为进一步确认B7-H3对MDSC的凋亡作用，本论文同时采用siRNA技术干预髓源性细胞株THP-1上B7-H3表达构建THP-1B7-H3low细胞以及THP-1-NC组，体外实验分析B7-H3缺失对髓源性细胞凋亡的影响。此外，本论文还在利用环磷酰胺抑制C57BL/6骨髓增殖的基础上，再次皮下移植接种RM-1-B7-H3转基因细胞以及RM-1-mock细胞，观察肿瘤生长情况，分析B7-H3发挥促瘤作用是否依赖于髓源性细胞。
结果：成功构建稳定表达、高效表达B7-H3的RM-1转基因细胞。体外实验RM-1-B7-H3转基因细胞以及RM-1-mock细胞在增殖能力方面两者并无统计学差异；然而，体内实验发现RM-1-B7-H3转基因细胞肿瘤生长显著高于RM-1-mock细胞。进一步研究发现，荷瘤RM-1-B7-H3的C57BL/6小鼠肿瘤组织及脾脏组织中Gr-1+CD11b+MDSC细胞数量显著高于RM-1-mock荷瘤小鼠；同时，本论文还发现RM-1-B7-H3荷瘤小鼠体内MDSC凋亡率显著低于RM-1-mock荷瘤小鼠。体外实验也证实RM-1-B7-H3细胞株与RM-1-mock细胞株相比，脾脏Gr-1+CD11b+MDSC凋亡率显著下降；人髓源性细胞株THP-1-B7-H3~(low)体外凋亡水平显著高于THP-1-B7-H3~(high)；上述结果提示B7-H3在抑制MDSC凋亡中发挥了重要作用。此外，环磷酰胺抑制骨髓造血后再次移植接种RM-1-B7-H3细胞株与RM-1-mock细胞株，构建前列腺癌荷瘤小鼠模型，两者之间的肿瘤生长差异并不存在，提示B7-H3促进前列腺癌生长依赖于髓源性细胞。
结论:众多研究均证实B7-H3高表达与前列腺癌进展密切相关，然而其中的作用机制并不清楚。本论文利用转基因技术构建B7-H3差异表达的RM-1细胞株，体内实验证实B7-H3可以促进小鼠前列腺癌细胞成瘤，其机制可能是B7-H3抑制髓源性抑制细胞凋亡，并通过聚集髓源性抑制细胞促进前列腺癌进展。
Objective: We regulated murine prostate cancer RM-1cells B7H3gene expressionusing gene transfection techniques. We observed mouse prostate cancer cell line of RM-1proliferation in the role of B7H3by in vivo and in vitro experiments, to explore its possiblemechanism.
Methods: We retrieved mice B7H3the nucleotide sequence, synthesized murineB7H3gene fragment, and transferred to the destination vector, using Gateway Technology.B7H3gene high expression plasmid vector was constructed. Transfected genes wereconsistent with the purpose of gene detected by gene sequencing. RT-PCR was used todetect mRNA expression before and after the plasmid construction. The above twomethods identified that the plasmids were successfully constructed. Prostate cancer in miceRM-1cells were stable transfection, and then transfected with plasmid vector B7H3geneRM-1cells as a control. Application observed by fluorescence microscopy transfected withgreen fluorescent protein expression to determine transfection success. After transfectionthe B7H3gene expression level was used to detect changes in mRNA expression byRT-PCR. The B7H3ene expression at the protein level changes in the two groups of cellswas detected by flow cytometry. Detection further confirmed that the B7H3gene wasstable transfection. In the part of in-vitro experiments,the RM-1cells were divided intotwo groups: the experimental group (B7-H3expression group) and negative control group(B7-H3low expression group only transfected with GFP). Cultured in vitro under the sameconditions, the murine prostate cancer cell changes were observated by counting thenumber of the cells. RM-1cell growth rate of the two groups were detected for comparingB7H3gene expression with low B7H3gene expression in mouse prostate cancer cellgrowth in vitro. Mice spleen was taken out and cut into pieces. The tissue was washed,then centrifuged into single cell suspension after grinding to obtain cell pellet. Add to Gr-1~+CD11b~+antibody on sorting by flow cytometry, MDSC was separated. Gr-1~+CD11b~+ cells from the spleen separation and purification were mixed culture with prostate cancerRM-1cells of the experimental group and the control group in vitro. The cells werecollected and detected by flow cytometry after cultured.We found the group of B7H3highexpression inhibit myeloid derived suppressor cell apoptosis in vitro. When THP-1cellsB7H3gene expression were lowered by small interfering RNA， marrow-derived myeloidTHP-1cell apoptosis were observed by flow cytometry. In the part of in vivoexperiments,high B7H3expression RM-1cells and low B7H3gene expression RM-1cellswere implanted in mice inguinal subcutaneous. Tumor growth was continuously observedafter implantion. The time of tumor formation and tumor size changes were recorded. Invivo testing to22days, experimental mice were sacrificed, and specimens were taken fromthe tumor and the spleen of experimental mice.The specimens were cut into smallpieces.After grinding and PBS fully washing blood cells and impurities, the specimenscentrifuged to obtain cell pellet. The cells were added to different antibodies on flowcytometry. B7H3gene expression and apoptosis were detected in transplanted tumor cellsand spleen cells. Myeloid derived suppressor cells expression and apoptosis were detected.Finally, cyclophosphamide was role in the spleen of experimental mice.to suppress bonemarrow lymphocytes. The size of the tumor volume changed by the B7H3gene expressionof experimental mice was observed without the interference of the bone marrow immunecells.
Results: The B7H3gene expression plasmid vector was successfully constructed.PCR amplification experiments confirmed that the the PCR identification bands around theplasmid construct theoretical size match the size of1200bp, with the purpose of Articlebelt. DNA sequencing showed that the nucleotide sequence of the insertion sites intoexperimental gene target gene fragment is entirely correct. The recombinant plasmidvectors by Gateway Technology B7H3gene were transducted into murine prostate cancerRM-1cells. The constructed plasmid B7H3support both at the mRNA level and at theprotein level could improve B7H3gene expression with the high transfection efficiency.After repeatedly subcultured the cells of the two experimental groups were extracted.Flowcytometry showed there are significant differences in the two groups of cells B7H3geneexpression. The experiment further confirmed that the B7H3gene was stable transfection.The in vitro cell growth rate results showed that the experimental group (B7-H3+group)and the negative control group RM-1cells were no significant difference. Purification Gr-1~+CD11b~+spleen cells were respectively mixed culture with RM-1prostate cancer cellsin mice of experimental group and control group. The cells were collected and detected byflow cytometry after cultured. B7-H3~+group, as compared to B7-H3-group, showedpreferentially inhibiting MDSC apoptosis. Marrow the endogenous THP-1cells apoptosisincidence rised after small interfering RNA reduced THP-1cells expression of humanB7H3. The two groups of mice prostate cancer cells were subcutaneously inoculated inmice groin. The tumorigenic time was recorded and tumor size were measured every twodays.There were significant differences in the two groups of tumor size. Tumors in miceappeared in B7H3gene high expression group earlier than the the B7H3genes lowexpression group.Tumor in experimental group grew faster than that in the controlgroup.The average tumor volume of experimental group increased significantly. Flowcytometry detected that the B7H3expression of mice transplanted tumor cells in B7H3gene regulation group was significantly increased. The in vivo experiments showed, theRM-1cells of B7H3gene regulation group in vivo tumorigenicity increased (P<0.01).After in Vivo cultured to22days, tumor-bearing mice were sacrificed by broken theneck. Specimens from tumor and spleen of experimental mice were extracted, recordingtumor volumes. Tumor cells and spleen cells were extracted from the two groups ofexperimental mice. The B7H3gene expression in tumor cells in mice inguinalsubcutaneous were detected by flow cytometry.That was also recorded including cellproliferation and apoptosis of myeloid derived suppressor cell proliferation and prostatecancer tumors in mice. The B7H3gene expression weakened after in vivo cultivation in thethe B7H3gene high expression group, but it was still higher than the B7H3gene lowexpression group.There was statistically significant difference between the two groups. Themyeloid derived suppressor cells of experimental group accelerated proliferation andapoptosis decreased while prostate cancer tumors in mice accelerated proliferation andapoptosis decreased. That was confirmed the B7H3gene in vivo promoted thedevelopment of tumors at the same time adjusted myeloid derived cells.The two groups ofexperimental mice were treated by Cyclophosphamide and then inoculated two groups ofprostate cancer cells RM-1in mice groin subcutaneous. There was no significant differencebetween the two groups of mice on transplanted tumor growth rate and size of tumor. Theexperiment proved B7H3promote tumor formation in vivo through the role of immunecells in the body.
Conclusions: The plasmid vector was constructed successfully，and B7H3gene wasstably transfected in RM-1cell line. That the stable transfection of B7H3gene expressionby plasmid-mediated was no obvious promotion RM-1cell apoptosis in vitro. But itinhibited RM-1cell growth; promoted the RM-1tumors in vivo tumorigenicity andprogress. B7H3gene stably transfected regulated MDSC to promote RM-1tumorprogression.The B7H3site is expected to become auxiliary potential target on gene therapyfor prostate cancer.
引文
1. Berglund RK，Masterson TA，Vora KC，et a1．Pathological upgrading and up stagingwith immediate repeat biopsy in patients eligible for active surveillance．J Ur．2008．180(5)：1964-1967．
2.叶定伟,李长岭, Ding-wei YE, Chang-ling LI.前列腺癌发病趋势的回顾和展望.中国癌症杂志.2007.17(3):177-180.
3.孙颖浩.我国前列腺癌的研究现状.中华泌尿外科杂志.2004.25(2):77-80.
4. Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control ofradical prostatectomy in men younger than50years of age: update2003. Urology.2003;62:86-91.
5. Carter HB,Epstein JI,Partin AW.Influence of age and prostate-specific antigen onthechance of curable prostate cancer among men with nonpalpable disease.Urology.1999.53(1):126-30.
6. ZhangHF, WangHL, Xu N, et a.l Mass screening of12027elderlymen for prostatecarcinoma by measuring serum prostate specific antigen [J]. ChinMed J (Engl),2004,117:67-70.
7. Quinn M,Babb P.Patterns and trends in prostate cancer incidence,survival,prevalenceand mortality.Part I:international comparisons.BJU Int.2002.90(2):162-73.
8. Lowe FC,Gilbert SM,Kahane H.Evidence of increased prostate cancer detectioninmen aged50to59:a review of324,684biopsies performed between1995and2002.Urology.2003.62(6):1045-9.
9. La Rosa F,Stracci F,Minelli L,Mastrandrea V.Epidemiology of prostate cancer in theUmbria region of Italy:evidence of opportunistic screening effects.Urology.2003.62(6):1040-4.
10. Boccon-Gibod L,Bertaccini A,Bono AV,et al.Management of locally advancedprostatecancer:a European consensus.Int J Clin Pract.2003.57(3):187-94.
11. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinicallylocalized prostate cancer: a multi-institutional pooled analysis. JAMA.1999;281:1598-604.
12. EAU guidelines on prostate cancer. Part1: screening, diagnosis, and treatment ofclinically localised disease. Eur Urol.2011Jan;59(1):61-71
13. Peyromaure M,Debre B,Mao K,et al.Management of prostate cancer in China:amulticenter report of6institutions.J Urol.2005.174(5):1794-7.
14. Bolla M,Collette L,Blank L,et al.Long-term results with immediate androgensuppression and external irradiation in patients with locally advanced prostatecancer(an EORTC study):a phase III randomised trial.Lancet.2002.360(9327):103-6.
15. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine comparedwith mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl JMed.2004;351:1513-20.
16. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantroneplus prednisone for advanced prostate cancer. N Engl J Med.2004;351:1502-12.
17. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression andsurvival rates following anatomical radical retropubic prostatectomy in3,478consecutive patients: long-term results. J Urol.2004;172:910-4..
18. Walsh PC.Surgery and the reduction of mortality from prostate cancer.N EnglJMed.2002.347(11):839-40.
19. Beerlage HP,Thuroff S,Madersbacher S,et al.Current status of minimally invasivetreatment options for localized prostate carcinoma.Eur Urol.2000.37(1):2-13.
20. Henry J,Miller MM,Pontarotti P.Structure and evolution of the extended B7family.Immunol Today.1999.20(6):285-8.
21. Chapoval AI,Ni J,Lau JS,et al.B7-H3:a costimulatory molecule for T cell activationand IFN-gamma production.Nat Immunol.2001.2(3):269-74.
22. Nagaraj S,Gupta K,Pisarev V,et al.Altered recognition of antigen is a mechanism ofCD8+T cell tolerance in cancer.Nat Med.2007.13(7):828-35.
23. Suh WK,Gajewska BU,Okada H,et al.The B7family member B7-H3preferentiallydown-regulates T helper type1-mediated immune responses.Nat Immunol.2003.4(9):899-906.
24. Roth TJ,Sheinin Y,Lohse CM,et al.B7-H3ligand expression by prostate cancer:anovel marker of prognosis and potential target for therapy.Cancer Res.2007.67(16):7893-900.
25. Zang X,Thompson RH,Al-Ahmadie HA,et al.B7-H3and B7x are highly expressed inhuman prostate cancer and associated with disease spread and poor outcome.Proc NatlAcad Sci U S A.2007.104(49):19458-63.
26. Steinberger P,Majdic O,Derdak SV,et al.Molecular characterization of human4Ig-B7-H3,a member of the B7family with four Ig-like domains.J Immunol.2004.172(4):2352-9.
27. Sun M,Richards S,Prasad DV,Mai XM,Rudensky A,Dong C.Characterization ofmouse and human B7-H3genes.J Immunol.2002.168(12):6294-7.9
28. Ling V,Wu PW,Spaulding V,et al.Duplication of primate and rodent B7-H3immunoglobulin V-and C-like domains:divergent history of functional redundancyand exon loss.Genomics.2003.82(3):365-77.
29. Zhang GB,Zhou H,Chen YJ,et al.Characterization and application of two novelmonoclonal antibodies against2IgB7-H3:expression analysis of2IgB7-H3ondendritic cells and tumor cells.Tissue Antigens.2005.66(2):83-92.
30. Waschbisch A,Wintterle S,Lochmuller H,et al.Human muscle cells express thecostimulatory molecule B7-H3,which modulates muscle-immune interactions.Arthritis Rheum.2008.58(11):3600-8.
31. Sun Y,Wang Y,Zhao J,et al.B7-H3and B7-H4expression in non-small-cell lungcancer.Lung Cancer.2006.53(2):143-51.
32. Lupu CM,Eisenbach C,Kuefner MA,et al.An orthotopic colon cancer model forstudying the B7-H3antitumor effect in vivo.J Gastrointest Surg.2006.10(5):635-45.
33. Crispen PL,Sheinin Y,Roth TJ,et al.Tumor cell and tumor vasculature expression ofB7-H3predict survival in clear cell renal cell carcinoma.Clin Cancer Res.2008.14(16):5150-7.
34. Lehmann BD,Paine MS,Brooks AM,et al.Senescence-associated exosome releasefrom human prostate cancer cells.Cancer Res.2008.68(19):7864-71.
35. Wu CP,Jiang JT,Tan M,et al.Relationship between co-stimulatory molecule B7-H3expression and gastric carcinoma histology and prognosis.World J Gastroenterol.2006.12(3):457-9.
36. Zhang G,Xu Y,Lu X,et al.Diagnosis value of serum B7-H3expression in non-smallcell lung cancer.Lung Cancer.2009.66(2):245-9.
37. Luo L,Chapoval AI,Flies DB,et al.B7-H3enhances tumor immunity in vivo bycostimulating rapid clonal expansion of antigen-specific CD8+cytolytic T cells.JImmunol.2004.173(9):5445-50.
38. Moore KW,de Waal Malefyt R,Coffman RL,O'Garra A.Interleukin-10and theinterleukin-10receptor.Annu Rev Immunol.2001.19:683-765.
39. Kim DH,Rossi JJ.Strategies for silencing human disease using RNA interference. NatRev Genet.2007.8(3):173-84.
40. McManus MT,Sharp PA.Gene silencing in mammals by small interfering RNAs. NatRev Genet.2002.3(10):737-47.
41. Chavin G,Sheinin Y,Crispen PL,et al.Expression of immunosuppresive B7-H3ligandby hormone-treated prostate cancer tumors and metastases.Clin Cancer Res.2009.15(6):2174-80.
42. Chen YW,Tekle C,Fodstad O.The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion.Curr CancerDrug Targets.2008.8(5):404-13.
43. Leitner J,Klauser C,Pickl WF,et al.B7-H3is a potent inhibitor of human T-cellactivation:No evidence for B7-H3and TREML2interaction.Eur J Immunol.2009.39(7):1754-64
44. Hashiguchi M,Kobori H,Ritprajak P,Kamimura Y,Kozono H,Azuma M.Triggeringreceptor expressed on myeloid cell-like transcript2(TLT-2)is a counter-receptor forB7-H3and enhances T cell responses.Proc Natl Acad Sci U SA.2008.105(30):10495-500.
45. Stern JN,Keskin DB,Barteneva N,Zuniga J,Yunis EJ,Ahmed AR.Possible role ofnatural killer cells in pemphigus vulgaris-preliminary observations.Clin Exp Immunol.2008.152(3):472-81.
46. Zhou GX,Ireland J,Rayman P,Finke J,Zhou M.Quantification of carbonic anhydraseIX expression in serum and tissue of renal cell carcinoma patients usingenzyme-linked immunosorbent assay:prognostic and diagnostic potentials.Urology.2010.75(2):257-61.
47. Tran CN,Thacker SG,Louie DM,et al.Interactions of T cells with fibroblast-likesynoviocytes:role of the B7family costimulatory ligand B7-H3.J Immunol.2008.180(5):2989-98.
1. Basherudin N,Curtis MD. Identification of positive GATEWAY expression cloneswhen both the pENTRY and pDEST vectors contain the same marker for bacterialselection. CSH Protoc.2006Nov1;2006(6).
2. Sone T,Yahata K,Sasaki Y, Multi-gene gateway clone design for expression ofmultiple heterologous genes in living cells: modular construction of multiple cDNAexpression elements using recombinant cloning. J Biotechnol.2008Sep10;136(3-4):113-21.
3. Fernandez AI, Viron N, Alhagdow M, Flexible tools for gene expression and silencingin tomato. Plant Physiol.2009Dec;151(4):1729-40.
4. Beem JE, Lee P, Segal MS. Lambda chops: creation of site-directed mutants ininsertable fragments utilizing Gateway technology. Mol Biotechnol.2009Jul;42(3):275-81.
5. Zou W. Immunosuppressive networks in the tumour environment and their therapeuticrelevance. Nat Rev Cancer.2005;5:263-74.
6. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol.2009;9:162-74.
7. Crispen PL, Sheinin Y, Roth TJ, et al. Tumor cell and tumor vasculature expression ofB7-H3predict survival in clearcell renal cell carcinoma. Clin Cancer Res.2008;14:5150-7.
8. Lehmann BD, Paine MS, Brooks AM et al. Senescence-associated exosome releasefrom human prostate cancer cells. Cancer Res.2008;68:7864-71.
9. Crispen PL, Sheinin Y, Roth TJ et al. Tumor cell and tumor vasculature expression ofB7-H3predict survival in clear cell renal cell carcinoma. Clin Cancer Res.2008;14:5150-7.
10. Zhang G, Dong Q, Xu Y et al. B7-H3: Another Molecule Marker for Mo-DCs?Cellular&Molecular Immunology.2005,2:307-11.
11. Roth TJ, Sheinin Y, Lohse CM et al. B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy. Cancer Res.2007;67:7893-900.
12. Zang X, Thompson RH, Al-Ahmadie HA et al. B7-H3and B7x are highly expressedin human prostate cancer and associated with disease spread and poor outcome. ProcNatl Acad Sci U S A.2007;104:19458-63.
13. Boorjian SA, Sheinin Y, Crispen PL et al. T-cell coregulatory molecule expression inurothelial cell carcinoma: clinicopathologic correlations and association with survival.Clin Cancer Res.2008;14:4800-8.
14. Zhang G, Chen Y, Shi Q et al. Human Recombinant B7-H3Expressed in E. coliEnhances T Lymphocyte Proliferation and IL-10Secretion in Vitro. Acta BiochimBiophys Sin (Shanghai).2004;36:430-6.
15. Ling V, Wu PW, Spaulding V et al. Duplication of primate and rodent B7-H3immunoglobulin V-and C-like domains: divergent history of functional redundancyand exon loss. Genomics.2003;82:365-77
16. Suh WK, Gajewska BU, Okada H et al. The B7family member B7-H3preferentiallydown-regulates T helper type1-mediated immune responses. Nat Immunol.2003;4:899-906.
17. Roberta C, Alessandra D, Raffaella A et al. Identification of4Ig-B7-H3as aneuroblastoma-associated molecule that exerts a protective role from an NKcell-mediated lysis. PNAS.2004;101:12640-5.
18.朱一蓓,张光波,周迎会等. B7-H3单抗交联作用对Mo-DC体外生物学功能的影响.现代免疫学.2008;28:116-20.
19. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity invivo by costimulating rapid clonal expansion of antigen-specific CD8+cytolytic Tcells,” Journal of Immunology, vol.173, no.9, pp.5445 5450,2004.
20. X. Sun, M. Vale, E. Leung, J. R. Kanwar, R. Gupta, and G. W. Krissansen,“MouseB7-H3induces antitumor immunity,” Gene Therapy, vol.10, no.20, pp.1728-1734,2003.
21. L. Ma, L. Luo, and L. Luo,“Complete eradication of hepatocellular carcinomas bycombined vasostatin gene therapy and B7H3-mediated immunotherapy,” Journal ofHepatology, vol.46, no.1, pp.98-106,2007.
22. Y. Sun, Y. Wang, J. Zhao, M. Gu, R. Giscombe, A. K. Lefvert, and X. Wang,“B7-H3and B7-H4expression in non-small-cell lung cancer,”Lung Cancer, vol.53, no.2, pp.143-151,2006.
23. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity invivo by costimulating rapid clonal expansion of antigen-specific CD8+cytolytic Tcells,” Journal of Immunology, vol.173, no.9, pp.5445-5450,2004.
24. P. L. Crispen, Y. Sheinin, and Y. Sheinin,“Tumor cell and tumor vasculatureexpression of B7-H3predict survival in clear cell renal cell carcinoma,” ClinicalCancer Research, vol.14, no.16, pp.5150-5157,2008.
25. T. J. Roth, Y. Sheinin, and Y. Sheinin,“B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy,”Cancer Research, vol.67,no.16, pp.7893-7900,2007.
26. X. Zang, P. S. Sullivan, and P. S. Sullivan,“Tumor associated endothelial expressionof B7-H3predicts survival in ovarian carcinomas,” Modern Pathology, vol.23, no.8,pp.1104-1112,2010.
27. J. Sun, L.-J. Chen, and L.-J. Chen,“Clinical significance and regulation of thecostimulatory molecule B7-H3in human colorectal carcinoma,” Cancer Immunology,Immunotherapy, vol.59, no.8, pp.1163-1171,2010.
28. Céspedes MV, Casanova I, Parre o M,et al. Mouse models in oncogenesis andcancer therapy[J]. Clin Transl Oncol,2006:8(5):318-329
29. Fujimura T, Mahnke K, Enk AH. Myeloid derived suppressor cells and their role intolerance induction in cancer. J Dermatol Sci.2010;59:1-6.
30. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol2009;9:162-74
31. Pan PY, Ma G, Weber KJ et al. Immune stimulatory receptor CD40is required forT-cell suppression and T regulatory cell activation mediated by myeloid-derivedsuppressor cells in cancer. Cancer Res.2010;70:99-108.
32. Yang R, Cai Z, Zhang Y et al. CD80in immune suppression by mouse ovariancarcinoma-associated Gr-1+CD11b+myeloidcells. Cancer Res.2006;66:6807-15.
33. Fujimura T, Ring S, Umansky V et al. Regulatory T Cells Stimulate B7-H1Expression in Myeloid-Derived Suppressor Cells in ret Melanomas. Invest Dermatol.2011; J doi:10.1038/jid.2011.
34. Mundy-Bosse BL, Lesinski GB, Jaime-Ramirez AC et al. Myeloid-derived suppressorcell inhibition of the IFN response in tumor-bearing mice. Cancer Res.2011;71:5101-10.
35. Fujita M, Kohanbash G, Fellows-Mayle W et al. COX-2blockade suppressesgliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res.2011;71:2664-74.
36. Obermajer N,Muthuswamy R,Odunsi K et al. PGE(2)-induced CXCL12productionand CXCR4expression controls the accumulation of human MDSCs in ovariancancer environment. Cancer Res.2011;71:7463-70.
37. Youn JI, Nagaraj S, Collazo M et al. Subsets of myeloid-derived suppressor cells intumor-bearing mice. J Immunol.2008;181:5791-802.
38. Corzo CA, Condamine T, Lu L et al. HIF-1α regulates function and differentiationof myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med.2010;207:2439-53.
39. Xu L, Zhang G, Zhou Y et al. Stimulation of B7-H3(CD276) directs thedifferentiation of human marrow stromal cells to osteoblasts. Immunobiology.2011;216:1311-7.
40. Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion. CurrCancer Drug Targets.2008;8:404-13.
41. Yuan H, Wei X, Zhang G et al. B7-h3over expression in prostate cancer promotestumor cell progression. The Journal of Urology.2011;186:1093-9.
42. Liu H, Tekle C, Chen YW, et al. B7-H3silencing increases paclitaxel sensitivity byabrogating Jak2/Stat3phosphorylation. Mol Cancer Ther.2011;10:960-71.
43. Jeannin P, Magistrelli G, Aubry JP et al.Soluble CD86is a costimulatory molecule forhuman T lymphocytes.Immunity.2000;13:303-312.
44. Oaks MK, Hallett KM. Cutting edge: a soluble form of CTLA-4in patients withautoimmune thyroid disease.J Immunol.2000,164:5015-5018.
45. Viallard JF, Solanilla A, Gauthier B et al.Increased soluble and platelet-associatedCD40ligand in essential thrombocythemia and reactive thrombocytosis. Blood.2002;99:2612-2614.
46. Wan B, Nie H, Liu A et al. Aberrant regulation of synovial T cell activation by solublecostimulatory molecules in rheumatoid arthritis. J Immunol.2006;177:8844-8850.
47. Wang Q, Chen Y, Xie F et al. Development of a sandwich ELISA for evaluatingsoluble OX40L(CD252)in human sera of different ages or with Graves'disease.Cytokine.2006;36:23-28.
48. Jung HW, Choi SW, Choi JI et al. Serum concentrations of soluble4-1BB and4-1BBligand correlated with the disease severity in rheumatoid arthritis. Exp MolMed.2003,36:13-22.
49. Watanabe N, Gavrieli M, Sedy JR et al. BTLA is a lymphocyte inhibitory receptorwith similarities to CTLA-4and PD-1. Nat Immunol.,2003,4:670-679.
50. Brandt CS, Baratin M, Yi EC et al. The B7family member B7-H6is a tumor cellligand for the activating natural killer cell receptor NKp30in humans. J Exp Med.2009;206:1495-503.
51. Goodwin RG, Din WS, Davis-Smith T, et al. Molecular cloning of a ligand for theinducible T cell gene4-1BB: a member of an emerging family of cytokines withhomology to tumor necrosis factor. Eur J Immunol.1993;23:2631-41.
52. Alderson MR, Craig AS, Tercsa, WT et al. Molecular and biological characterizationof human4-1bb and its ligand. Eur J Immunol.1994;24:2219-27.
53. Godfrey WR, Fagnoni FF, Harara MA et al. Identification of a human OX-40ligand, acostimulator of CD4+T cells with homology to tumor necrosis factor. J Exp Med.1994;180:757-62.
54. Coyle A, Gutierrez-Ramps J. The expanding B7superfanuly: Increasing complexityin costimulatory signals regulating T cell function. Nat Immunol.2001;2:203-9.
55. Greenwald RJ, Freeman GJ, Sharpe AH.The B7family revisited.Annu RevImmunol.2005;23:515-48.
56. Ishida Y, Agata Y, Shibahara Ket al.Induced expression of PD-1,a novel member ofthe immunoglobulin gene superfamily,upon programmed cell death. EMBO.1992;11:3887-95.
57. Dong H, Zhu G, Tamada K, Chen L et al. B7.H1, a third member of the B7family,costimulates T-cell proliferation and secretion of interleukin-10. Nat Med.1999;5:1365-9.
58. Latchman Y, Wood CR, Chernova T et al. PD-L2is a second ligand for PD-1andinhibits T cell activation. Nat Immunol.2001;2:261-9.
59. Dong H, Strome SE, Salomao DR et al. Tumor-associated B7-H1promotes T cellapoptosis: a potential mechanism of immune evasion. Nat Med.2002;8:793-800.
60. Wang S, Zhu G, Chapoval AI et al. Costimulation of T cells by B7-H2, a B7-likemolecule that binds ICOS. Blood.2000;96:2808-13.
61. Yoshinaga S K, Whoriskey JS, Khare SD et al. T-cell co-stimulation through B7RP-1and ICOS. Nature.1999;402:827-32.
62. Swallow MM, Wallin JJ, Sha WC et al. B7h, a novel costimulatory homolog of B7.1and B7.2, is induced by TNF-α. Immunity.1999;11:423-32.
63. Hutloff A, Dittrich AM, Beier KC et al. ICOS is an inducible T-cell co-stimulatorstructurally and functionally related to CD28. Nature.1999;397:263-6.
64. Sica GL, Choi IH, Zhu G et al. B7-H4, a molecule of the B7family, negativelyregulates T cell immunity. Immunity.2003;18:849-61.
65. Chapoval AI, Ni J, Lau JS et al. B7-H3: a costimulatory molecule for T cell activationand IFN-γ production. Nat. Immunol.,2001;2:269-74.
66. Prasad DV, Richards S, Mai XM et al. B7S1, a novel B7family member thatnegatively regulates T cell activation. Immunity.2003;18:863-73.
67. Zang X, Loke P, Kim J et al. B7x: a widely expressed B7family member that inhibitsT cell activation. Proc. Natl. Acad. Sci.,2003;100:10388-92.
68. Watts TH.TNF/TNFR family members in costimulation of T cell responses. Annu RevImmunol.2005;23:23-68.
69. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7SYSTEM OF T CELLCOSTIMULATION. Annu. Rev. Immunol.,1996;14:233-258.
70. Chen L. Co-inhibitory molecules of the B7-CD28family in the control of T-cellimmunity. Nat Rev Immunol.2004;4:336-347.
71. Bretscher PA, Coln M.A theory of self and non selfdiscrimination. Science.1970;169:1042-1049.
72. Bretscher PA. A two-step, two-signal model for the primary activation of precursorhelper T cells. Proc. Natl Acad. Sci.,1999,96:185 190.
73. Hodge JW, Greiner JW, Tsang KYet al. Costimulatory molecules as adjuvants forimmunotherapy. Front Biosci.2006;11:788-803.
74. Greenwald RJ, Freeman GJ, Sharpe AH.The B7family revisited.Annu Rev Immunol.2005;23:515-548.
1. A. K. Abbas,“The control of T cell activation vs. tolerance,” Autoimmunity Reviews,vol.2, no.3, pp.115–118,2003.
2. L. Chen, et al.“Co-inhibitory molecules of the B7-CD28family in the control of T-cellimmunity,” Nature Reviews Immunology, vol.4, no.5, pp.336–347,2004.
3. R. J. Greenwald, G. J. Freeman, and A. H. Sharpe,“The B7family revisited,” AnnualReview of Immunology, vol.23, pp.515–548,2005.
4. M. Loos, N. A. Giese, and N. A. Giese,“Clinical significance and regulation of thecostimulatory molecule B7-H1in pancreatic cancer,” Cancer Letters, vol.268, no.1,pp.98–109,2008.
5. J. Konishi, K. Yamazaki, M. Azuma, I. Kinoshita, H. Dosaka-Akita, and M. Nishimura,“B7-H1expression on non-small cell lung cancer cells and its relationship withtumor-infiltrating lymphocytes and their PD-1expression,” Clinical Cancer Research,vol.10, no.15, pp.5094–5100,2004.
6. Y. Liu, B. Zeng, Z. Zhang, Y. Zhang, and R. Yang,“B7-H1on myeloid-derivedsuppressor cells in immune suppression by a mouse model of ovarian cancer,” ClinicalImmunology, vol.129, no.3, pp.471–481,2008.
7. H. Ghebeh, S. Mohammed, and S. Mohammed,“The B7-H1(PD-L1) Tlymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltratingductal carcinoma: correlation with important high-risk prognostic factors,” Neoplasia,vol.8, no.3, pp.190–198,2006.
8. R.H.Thompson, M. D. Gillett, and M. D. Gillett,“Costimulatory B7-H1in renal cellcarcinoma patients: indicator of tumor aggressiveness and potential therapeutic target,”Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.49, pp.17174–17179,2004.
9. E. J. Small, N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison,“Apilot trial of CTLA-4blockade with human anti-CTLA-4in patients withhormone-refractory prostate cancer,” Clinical Cancer Research, vol.13, no.6, pp.1810–1815,2007.
10. E. D. Kwon, B. A. Foster, A. A. Hurwitz, C. Madias, J. P. Allison, N. M. Greenberg,and M. B. Burg,“Elimination of residual metastatic prostate cancer after surgery andadjunctive cytotoxic T lymphocyte-associated antigen4(CTLA-4) blockadeimmunotherapy,” Proceedings of the National Academy of Sciences of the UnitedStates of America, vol.96, no.26, pp.15074–15079,1999.
11. M. R. Theoret, P. M. Arlen, M. Pazdur, W. L. Dahut, J. Schlom, and J. L. Gulley,“Phase I trial of an enhanced prostate-specific antigen-based vaccine and anti-CTLA-4antibody in patients with metastatic androgen-independent prostate cancer,” ClinicalGenitourinary Cancer, vol.5, no.5, pp.347–350,2007.
12. C. I. Liakou, A. Kamat, and A. Kamat,“CTLA-4blockade increases IFNγ-producingCD4+ICOS hi cells to shift the ratio of effector to regulatory T cells in cancerpatients,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.105, no.39, pp.14987–14992,2008.
13. R. H. Thompson, J. P. Allison, and E. D. Kwon,“Anti-cytotoxic T lymphocyteantigen-4(CTLA-4) immunotherapy for the treatment of prostate cancer,” UrologicOncology, vol.24, no.5, pp.442–447,2006.
14. J. A. Blansfield, K. E. Beck, and K. E. Beck,“Cytotoxic T-lymphocyte-associatedantigen-4blockage can induce autoimmune hypophysitis in patients with metastaticmelanoma and renal cancer,” Journal of Immunotherapy, vol.28, no.6, pp.593–598,2005.
15. J. Yuan, S. Gnjatic, and S. Gnjatic,“CTLA-4blockade enhances polyfunctionalNY-ESO-1specific T cell responses in metastatic melanoma patients with clinicalbenefit,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.105, no.51, pp.20410–20415,2008.
16. D. O'Mahony, J. C. Morris, and J. C. Morris,“A pilot study of CTLA-4blockade aftercancer vaccine failure in patients with advanced malignancy,” Clinical CancerResearch, vol.13, no.3, pp.958–964,2007.
17. S. M. Ansell, S. A. Hurvitz, and S. A. Hurvitz,“Phase I study of ipilimumab, ananti-CTLA-4monoclonal antibody, in patients with relapsed and refractory B-cellnon-Hodgkin lymphoma,” Clinical Cancer Research, vol.15, no.20, pp.6446–6453,2009.
18. A.I. Chapoval, J. Ni, and J. Ni,“B7-H3: a costimulatory molecule for T cell activationand IFN-γ production,” Nature Immunology, vol.2, no.3, pp.269–274,2001.
19. R. Castriconi, A. Dondero, and A. Dondero,“Identification of4Ig-B7-H3as aneuroblastoma-associated molecule that exerts a protective role from an NKcell-mediated lysis,” Proceedings of the National Academy of Sciences of the UnitedStates of America, vol.101, no.34, pp.12640–12645,2004.
20. P. Steinberger, O. Majdic, and O. Majdic,“Molecular characterization of human4Ig-B7-H3, a member of the B7family with four Ig-like domains,” Journal ofImmunology, vol.172, no.4, pp.2352–2359,2004.
21. M. Hashiguchi, H. Kobori, P. Ritprajak, Y. Kamimura, H. Kozono, and M. Azuma,“Triggering receptor expressed on myeloid cell-like transcript2(TLT-2) is acounter-receptor for B7-H3and enhances T cell responses,” Proceedings of theNational Academy of Sciences of the United States of America, vol.105, no.30, pp.10495–10500,2008.
22. J. Klesney-Tait, I. R. Turnbull, and M. Colonna,“The TREM receptor family andsignal integration,” Nature Immunology, vol.7, no.12, pp.1266–1273,2006.
23. J. Leitner, C. Klauser, and C. Klauser,“B7-H3is a potent inhibitor of human T-cellactivation: no evidence for B7-H3and TREML2interaction,” European Journal ofImmunology, vol.39, no.7, pp.1754–1764,2009.
24. Y. Sun, Y. Wang, J. Zhao, M. Gu, R. Giscombe, A. K. Lefvert, and X. Wang,“B7-H3and B7-H4expression in non-small-cell lung cancer,” Lung Cancer, vol.53, no.2, pp.143–151,2006.
25. M. Loos, D. M. Hedderich, and D. M. Hedderich,“Expression of the costimulatorymolecule B7-H3is associated with prolonged survival in human pancreatic cancer,”BMC Cancer, vol.9, article463,2009.
26. X.-P. Wu, J.-T. Jiang, and J.-T. Jiang,“Relationship between co-stimulatory molecueB7-H3expression and gastric carcinoma histology and prognosis,” World Journal ofGastroenterology, vol.12, no.3, pp.457–459,2006.
27. X. Zang, P. S. Sullivan, and P. S. Sullivan,“Tumor associated endothelial expressionof B7-H3predicts survival in ovarian carcinomas,” Modern Pathology, vol.23, no.8,pp.1104–1112,2010.
28. P. L. Crispen, Y. Sheinin, and Y. Sheinin,“Tumor cell and tumor vasculatureexpression of B7-H3predict survival in clear cell renal cell carcinoma,” ClinicalCancer Research, vol.14, no.16, pp.5150–5157,2008.
29. J. Sun, L.-J. Chen, and L.-J. Chen,“Clinical significance and regulation of thecostimulatory molecule B7-H3in human colorectal carcinoma,” Cancer Immunology,Immunotherapy, vol.59, no.8, pp.1163–1171,2010.
30. S. A. Boorjian, Y. Sheinin, and Y. Sheinin,“T-Cell coregulatory molecule expressionin urothelial cell carcinoma: clinicopathologic correlations and association withsurvival,” Clinical Cancer Research, vol.14, no.15, pp.4800–4808,2008.
31. T. J. Roth, Y. Sheinin, and Y. Sheinin,“B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy,” Cancer Research, vol.67,no.16, pp.7893–7900,2007.
32. L. Wang, C. C. Fraser, and C. C. Fraser,“B7-H3promotes acute and chronic allograftrejection,” European Journal of Immunology, vol.35, no.2, pp.428–438,2005.
33. Nagashima, N. Harada, and N. Harada,“B7-H3contributes to the development ofpathogenic Th2cells in a murine model of asthma,” Journal of Immunology, vol.181,no.6, pp.4062–4071,2008.
34. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity in vivoby costimulating rapid clonal expansion of antigen-specific CD8+cytolytic T cells,”Journal of Immunology, vol.173, no.9, pp.5445–5450,2004.
35. X. Sun, M. Vale, E. Leung, J. R. Kanwar, R. Gupta, and G. W. Krissansen,“MouseB7-H3induces antitumor immunity,” Gene Therapy, vol.10, no.20, pp.1728–1734,2003.
36. C. M. Lupu, C. Eisenbach, A. D. Lupu, M. A. Kuefner, B. Hoyler, W. Stremmel, and J.Encke,“Adenoviral B7-H3therapy induces tumor specific immune responses andreduces secondary metastasis in a murine model of colon cancer,” Oncology reports,vol.18, no.3, pp.745–748,2007.
37. L. Ma, L. Luo, and L. Luo,“Complete eradication of hepatocellular carcinomas bycombined vasostatin gene therapy and B7H3-mediated immunotherapy,” Journal ofHepatology, vol.46, no.1, pp.98–106,2007.
38. W.-K. Suh, B. U. Gajewska, and B. U. Gajewska,“The B7family member B7-H3preferentially down-regulates T helper type1-mediated immune responses,” NatureImmunology, vol.4, no.9, pp.899–906,2003.
39. D. V. R. Prasad, T. Nguyen, Z. Li, Y. Yang, J. Duong, Y. Wang, and C. Dong,“MurineB7-H3is a negative regulator of T cells,” Journal of Immunology, vol.173, no.4, pp.2500–2506,2004.
40. A.Fukushima, T.Sumi, and T. Sumi,“B7-H3regulates the development ofexperimental allergic conjunctivitis in mice,” Immunology Letters, vol.113, no.1, pp.52–57,2007.
41. K. Mahnke, S. Ring, and S. Ring,“Induction of immunosuppressive functions ofdendritic cells in vivo by CD4+CD25+regulatory T cells: role of B7-H3expressionand antigen presentation,” European Journal of Immunology, vol.37, no.8, pp.2117–2126,2007.
42. G. Zhang, Y. Xu, X. Lu, H. Huang, Y. Zhou, B. Lu, and X. Zhang,“Diagnosis value ofserum B7-H3expression in non-small cell lung cancer,” Lung Cancer, vol.66, no.2,pp.245–249,2009.
43. X. Zang, R. H. Thompson, and R. H. Thompson,“B7-H3and B7x are highlyexpressed in human prostate cancer and associated with disease spread and pooroutcome,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.104, no.49, pp.19458–19463,2007.
44. S. A. Boorjian, Y. Sheinin, P. L. Crispen, C. M. Lohse, B. C. Leibovich, and E. D.Kwon,“T-cell co-regulatory molecule expression in renal angiomyolipoma andpulmonary lymphangioleiomyomatosis,” Urology, vol.74, no.6, pp.1359–1364,2009.
45. Gregorio, M. V. Corrias, and M. V. Corrias,“Small round blue cell tumours: diagnosticand prognostic usefulness of the expression of B7-H3surface molecule,”Histopathology, vol.53, no.1, pp.73–80,2008.
46. S. Parker, M. G. Heckman, and M. G. Heckman,“Evaluation of B7-H3expression as abiomarker of biochemical recurrence after salvage radiation therapy for recurrentprostate cancer,” International Journal of Radiation Oncology, Biology, Physics. Inpress.
47. Yamato, M. Sho, and M. Sho,“Clinical importance of B7-H3expression in humanpancreatic cancer,” British Journal of Cancer, vol.101, no.10, pp.1709–1716,2009.
48. Tirapu, E. Huarte, and E. Huarte,“Low surface expression of B7-1(CD80) is animmunoescape mechanism of colon carcinoma,” Cancer Research, vol.66, no.4, pp.2442–2450,2006.
49. K. H. Yi and L. Chen,“Fine tuning the immune response through B7-H3and B7-H4,”Immunological Reviews, vol.229, no.1, pp.145–151,2009.
50. T. Sun, Z. Hu, H. Shen, and D. Lin,“Genetic polymorphisms in cytotoxicT-lymphocyte antigen4and cancer: the dialectical nature of subtle human immunedysregulation,” Cancer Research, vol.69, no.15, pp.6011–6014,2009.
51. Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion. Curr CancerDrug Targets.2008;8:404-13.
52. Yuan H, Wei X, Zhang G et al. B7-h3over expression in prostate cancer promotestumor cell progression. The Journal of Urology.2011;186:1093-9.
53. Xu L, Zhang G, Zhou Y et al. Stimulation of B7-H3(CD276) directs thedifferentiation of human marrow stromal cells to osteoblasts. Immunobiology.2011;216:1311-7.
54. Liu H, Tekle C, Chen YW, et al. B7-H3silencing increases paclitaxel sensitivity byabrogating Jak2/Stat3phosphorylation. Mol Cancer Ther.2011;10:960-71
55. M. Z. Dewan, A. E. Galloway, N. Kawashima, J. K. Dewyngaert, J. S. Babb, S. C.Formenti, and S. Demaria,“Fractionated but not single-dose radiotherapy induces animmune-mediated abscopal effect when combined with anti-CTLA-4antibody,”Clinical Cancer Research, vol.15, no.17, pp.5379–5388,2009.
56. A.V. Maker, G. Q. Phan, and G. Q. Phan,“Tumor regression and autoimmunity inpatients treated with cytotoxic T lymphocyte-associated antigen4blockade andinterleukin2: a phase I/II study,” Annals of Surgical Oncology, vol.12, no.12, pp.1005–1016,2005.
57. F. S. Hodi, M. C. Mihm, and M. C. Mihm,“Biologic activity of cytotoxic Tlymphocyte-associated antigen4antibody blockade in previously vaccinatedmetastatic melanoma and ovarian carcinoma patients,” Proceedings of the NationalAcademy of Sciences of the United States of America, vol.100, no.8, pp.4712–4717,2003.
58. H. J. J. van der Vliet, H. B. Koon, and H. B. Koon,“Effects of the administration ofhigh-dose interleukin-2on immunoregulatory cell subsets in patients with advancedmelanoma and renal cell cancer,” Clinical Cancer Research, vol.13, no.7, pp.2100–2108,2007.
59. J. R. Brahmer, C. G. Drake, and C. G. Drake,“Phase I study of single-agentanti-programmed death-1(MDX-1106) in refractory solid tumors: safety, clinicalactivity, pharmacodynamics, and immunologic correlates,” Journal of ClinicalOncology, vol.28, no.19, pp.3167–3175,2010.
2.叶定伟,李长岭, Ding-wei YE, Chang-ling LI.前列腺癌发病趋势的回顾和展望.中国癌症杂志.2007.17(3):177-180.
3.孙颖浩.我国前列腺癌的研究现状.中华泌尿外科杂志.2004.25(2):77-80.
4. Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control ofradical prostatectomy in men younger than50years of age: update2003. Urology.2003;62:86-91.
5. Carter HB,Epstein JI,Partin AW.Influence of age and prostate-specific antigen onthechance of curable prostate cancer among men with nonpalpable disease.Urology.1999.53(1):126-30.
6. ZhangHF, WangHL, Xu N, et a.l Mass screening of12027elderlymen for prostatecarcinoma by measuring serum prostate specific antigen [J]. ChinMed J (Engl),2004,117:67-70.
7. Quinn M,Babb P.Patterns and trends in prostate cancer incidence,survival,prevalenceand mortality.Part I:international comparisons.BJU Int.2002.90(2):162-73.
8. Lowe FC,Gilbert SM,Kahane H.Evidence of increased prostate cancer detectioninmen aged50to59:a review of324,684biopsies performed between1995and2002.Urology.2003.62(6):1045-9.
9. La Rosa F,Stracci F,Minelli L,Mastrandrea V.Epidemiology of prostate cancer in theUmbria region of Italy:evidence of opportunistic screening effects.Urology.2003.62(6):1040-4.
10. Boccon-Gibod L,Bertaccini A,Bono AV,et al.Management of locally advancedprostatecancer:a European consensus.Int J Clin Pract.2003.57(3):187-94.
11. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinicallylocalized prostate cancer: a multi-institutional pooled analysis. JAMA.1999;281:1598-604.
12. EAU guidelines on prostate cancer. Part1: screening, diagnosis, and treatment ofclinically localised disease. Eur Urol.2011Jan;59(1):61-71
13. Peyromaure M,Debre B,Mao K,et al.Management of prostate cancer in China:amulticenter report of6institutions.J Urol.2005.174(5):1794-7.
14. Bolla M,Collette L,Blank L,et al.Long-term results with immediate androgensuppression and external irradiation in patients with locally advanced prostatecancer(an EORTC study):a phase III randomised trial.Lancet.2002.360(9327):103-6.
15. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine comparedwith mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl JMed.2004;351:1513-20.
16. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantroneplus prednisone for advanced prostate cancer. N Engl J Med.2004;351:1502-12.
17. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression andsurvival rates following anatomical radical retropubic prostatectomy in3,478consecutive patients: long-term results. J Urol.2004;172:910-4..
18. Walsh PC.Surgery and the reduction of mortality from prostate cancer.N EnglJMed.2002.347(11):839-40.
19. Beerlage HP,Thuroff S,Madersbacher S,et al.Current status of minimally invasivetreatment options for localized prostate carcinoma.Eur Urol.2000.37(1):2-13.
20. Henry J,Miller MM,Pontarotti P.Structure and evolution of the extended B7family.Immunol Today.1999.20(6):285-8.
21. Chapoval AI,Ni J,Lau JS,et al.B7-H3:a costimulatory molecule for T cell activationand IFN-gamma production.Nat Immunol.2001.2(3):269-74.
22. Nagaraj S,Gupta K,Pisarev V,et al.Altered recognition of antigen is a mechanism ofCD8+T cell tolerance in cancer.Nat Med.2007.13(7):828-35.
23. Suh WK,Gajewska BU,Okada H,et al.The B7family member B7-H3preferentiallydown-regulates T helper type1-mediated immune responses.Nat Immunol.2003.4(9):899-906.
24. Roth TJ,Sheinin Y,Lohse CM,et al.B7-H3ligand expression by prostate cancer:anovel marker of prognosis and potential target for therapy.Cancer Res.2007.67(16):7893-900.
25. Zang X,Thompson RH,Al-Ahmadie HA,et al.B7-H3and B7x are highly expressed inhuman prostate cancer and associated with disease spread and poor outcome.Proc NatlAcad Sci U S A.2007.104(49):19458-63.
26. Steinberger P,Majdic O,Derdak SV,et al.Molecular characterization of human4Ig-B7-H3,a member of the B7family with four Ig-like domains.J Immunol.2004.172(4):2352-9.
27. Sun M,Richards S,Prasad DV,Mai XM,Rudensky A,Dong C.Characterization ofmouse and human B7-H3genes.J Immunol.2002.168(12):6294-7.9
28. Ling V,Wu PW,Spaulding V,et al.Duplication of primate and rodent B7-H3immunoglobulin V-and C-like domains:divergent history of functional redundancyand exon loss.Genomics.2003.82(3):365-77.
29. Zhang GB,Zhou H,Chen YJ,et al.Characterization and application of two novelmonoclonal antibodies against2IgB7-H3:expression analysis of2IgB7-H3ondendritic cells and tumor cells.Tissue Antigens.2005.66(2):83-92.
30. Waschbisch A,Wintterle S,Lochmuller H,et al.Human muscle cells express thecostimulatory molecule B7-H3,which modulates muscle-immune interactions.Arthritis Rheum.2008.58(11):3600-8.
31. Sun Y,Wang Y,Zhao J,et al.B7-H3and B7-H4expression in non-small-cell lungcancer.Lung Cancer.2006.53(2):143-51.
32. Lupu CM,Eisenbach C,Kuefner MA,et al.An orthotopic colon cancer model forstudying the B7-H3antitumor effect in vivo.J Gastrointest Surg.2006.10(5):635-45.
33. Crispen PL,Sheinin Y,Roth TJ,et al.Tumor cell and tumor vasculature expression ofB7-H3predict survival in clear cell renal cell carcinoma.Clin Cancer Res.2008.14(16):5150-7.
34. Lehmann BD,Paine MS,Brooks AM,et al.Senescence-associated exosome releasefrom human prostate cancer cells.Cancer Res.2008.68(19):7864-71.
35. Wu CP,Jiang JT,Tan M,et al.Relationship between co-stimulatory molecule B7-H3expression and gastric carcinoma histology and prognosis.World J Gastroenterol.2006.12(3):457-9.
36. Zhang G,Xu Y,Lu X,et al.Diagnosis value of serum B7-H3expression in non-smallcell lung cancer.Lung Cancer.2009.66(2):245-9.
37. Luo L,Chapoval AI,Flies DB,et al.B7-H3enhances tumor immunity in vivo bycostimulating rapid clonal expansion of antigen-specific CD8+cytolytic T cells.JImmunol.2004.173(9):5445-50.
38. Moore KW,de Waal Malefyt R,Coffman RL,O'Garra A.Interleukin-10and theinterleukin-10receptor.Annu Rev Immunol.2001.19:683-765.
39. Kim DH,Rossi JJ.Strategies for silencing human disease using RNA interference. NatRev Genet.2007.8(3):173-84.
40. McManus MT,Sharp PA.Gene silencing in mammals by small interfering RNAs. NatRev Genet.2002.3(10):737-47.
41. Chavin G,Sheinin Y,Crispen PL,et al.Expression of immunosuppresive B7-H3ligandby hormone-treated prostate cancer tumors and metastases.Clin Cancer Res.2009.15(6):2174-80.
42. Chen YW,Tekle C,Fodstad O.The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion.Curr CancerDrug Targets.2008.8(5):404-13.
43. Leitner J,Klauser C,Pickl WF,et al.B7-H3is a potent inhibitor of human T-cellactivation:No evidence for B7-H3and TREML2interaction.Eur J Immunol.2009.39(7):1754-64
44. Hashiguchi M,Kobori H,Ritprajak P,Kamimura Y,Kozono H,Azuma M.Triggeringreceptor expressed on myeloid cell-like transcript2(TLT-2)is a counter-receptor forB7-H3and enhances T cell responses.Proc Natl Acad Sci U SA.2008.105(30):10495-500.
45. Stern JN,Keskin DB,Barteneva N,Zuniga J,Yunis EJ,Ahmed AR.Possible role ofnatural killer cells in pemphigus vulgaris-preliminary observations.Clin Exp Immunol.2008.152(3):472-81.
46. Zhou GX,Ireland J,Rayman P,Finke J,Zhou M.Quantification of carbonic anhydraseIX expression in serum and tissue of renal cell carcinoma patients usingenzyme-linked immunosorbent assay:prognostic and diagnostic potentials.Urology.2010.75(2):257-61.
47. Tran CN,Thacker SG,Louie DM,et al.Interactions of T cells with fibroblast-likesynoviocytes:role of the B7family costimulatory ligand B7-H3.J Immunol.2008.180(5):2989-98.
1. Basherudin N,Curtis MD. Identification of positive GATEWAY expression cloneswhen both the pENTRY and pDEST vectors contain the same marker for bacterialselection. CSH Protoc.2006Nov1;2006(6).
2. Sone T,Yahata K,Sasaki Y, Multi-gene gateway clone design for expression ofmultiple heterologous genes in living cells: modular construction of multiple cDNAexpression elements using recombinant cloning. J Biotechnol.2008Sep10;136(3-4):113-21.
3. Fernandez AI, Viron N, Alhagdow M, Flexible tools for gene expression and silencingin tomato. Plant Physiol.2009Dec;151(4):1729-40.
4. Beem JE, Lee P, Segal MS. Lambda chops: creation of site-directed mutants ininsertable fragments utilizing Gateway technology. Mol Biotechnol.2009Jul;42(3):275-81.
5. Zou W. Immunosuppressive networks in the tumour environment and their therapeuticrelevance. Nat Rev Cancer.2005;5:263-74.
6. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol.2009;9:162-74.
7. Crispen PL, Sheinin Y, Roth TJ, et al. Tumor cell and tumor vasculature expression ofB7-H3predict survival in clearcell renal cell carcinoma. Clin Cancer Res.2008;14:5150-7.
8. Lehmann BD, Paine MS, Brooks AM et al. Senescence-associated exosome releasefrom human prostate cancer cells. Cancer Res.2008;68:7864-71.
9. Crispen PL, Sheinin Y, Roth TJ et al. Tumor cell and tumor vasculature expression ofB7-H3predict survival in clear cell renal cell carcinoma. Clin Cancer Res.2008;14:5150-7.
10. Zhang G, Dong Q, Xu Y et al. B7-H3: Another Molecule Marker for Mo-DCs?Cellular&Molecular Immunology.2005,2:307-11.
11. Roth TJ, Sheinin Y, Lohse CM et al. B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy. Cancer Res.2007;67:7893-900.
12. Zang X, Thompson RH, Al-Ahmadie HA et al. B7-H3and B7x are highly expressedin human prostate cancer and associated with disease spread and poor outcome. ProcNatl Acad Sci U S A.2007;104:19458-63.
13. Boorjian SA, Sheinin Y, Crispen PL et al. T-cell coregulatory molecule expression inurothelial cell carcinoma: clinicopathologic correlations and association with survival.Clin Cancer Res.2008;14:4800-8.
14. Zhang G, Chen Y, Shi Q et al. Human Recombinant B7-H3Expressed in E. coliEnhances T Lymphocyte Proliferation and IL-10Secretion in Vitro. Acta BiochimBiophys Sin (Shanghai).2004;36:430-6.
15. Ling V, Wu PW, Spaulding V et al. Duplication of primate and rodent B7-H3immunoglobulin V-and C-like domains: divergent history of functional redundancyand exon loss. Genomics.2003;82:365-77
16. Suh WK, Gajewska BU, Okada H et al. The B7family member B7-H3preferentiallydown-regulates T helper type1-mediated immune responses. Nat Immunol.2003;4:899-906.
17. Roberta C, Alessandra D, Raffaella A et al. Identification of4Ig-B7-H3as aneuroblastoma-associated molecule that exerts a protective role from an NKcell-mediated lysis. PNAS.2004;101:12640-5.
18.朱一蓓,张光波,周迎会等. B7-H3单抗交联作用对Mo-DC体外生物学功能的影响.现代免疫学.2008;28:116-20.
19. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity invivo by costimulating rapid clonal expansion of antigen-specific CD8+cytolytic Tcells,” Journal of Immunology, vol.173, no.9, pp.5445 5450,2004.
20. X. Sun, M. Vale, E. Leung, J. R. Kanwar, R. Gupta, and G. W. Krissansen,“MouseB7-H3induces antitumor immunity,” Gene Therapy, vol.10, no.20, pp.1728-1734,2003.
21. L. Ma, L. Luo, and L. Luo,“Complete eradication of hepatocellular carcinomas bycombined vasostatin gene therapy and B7H3-mediated immunotherapy,” Journal ofHepatology, vol.46, no.1, pp.98-106,2007.
22. Y. Sun, Y. Wang, J. Zhao, M. Gu, R. Giscombe, A. K. Lefvert, and X. Wang,“B7-H3and B7-H4expression in non-small-cell lung cancer,”Lung Cancer, vol.53, no.2, pp.143-151,2006.
23. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity invivo by costimulating rapid clonal expansion of antigen-specific CD8+cytolytic Tcells,” Journal of Immunology, vol.173, no.9, pp.5445-5450,2004.
24. P. L. Crispen, Y. Sheinin, and Y. Sheinin,“Tumor cell and tumor vasculatureexpression of B7-H3predict survival in clear cell renal cell carcinoma,” ClinicalCancer Research, vol.14, no.16, pp.5150-5157,2008.
25. T. J. Roth, Y. Sheinin, and Y. Sheinin,“B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy,”Cancer Research, vol.67,no.16, pp.7893-7900,2007.
26. X. Zang, P. S. Sullivan, and P. S. Sullivan,“Tumor associated endothelial expressionof B7-H3predicts survival in ovarian carcinomas,” Modern Pathology, vol.23, no.8,pp.1104-1112,2010.
27. J. Sun, L.-J. Chen, and L.-J. Chen,“Clinical significance and regulation of thecostimulatory molecule B7-H3in human colorectal carcinoma,” Cancer Immunology,Immunotherapy, vol.59, no.8, pp.1163-1171,2010.
28. Céspedes MV, Casanova I, Parre o M,et al. Mouse models in oncogenesis andcancer therapy[J]. Clin Transl Oncol,2006:8(5):318-329
29. Fujimura T, Mahnke K, Enk AH. Myeloid derived suppressor cells and their role intolerance induction in cancer. J Dermatol Sci.2010;59:1-6.
30. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of theimmune system. Nat Rev Immunol2009;9:162-74
31. Pan PY, Ma G, Weber KJ et al. Immune stimulatory receptor CD40is required forT-cell suppression and T regulatory cell activation mediated by myeloid-derivedsuppressor cells in cancer. Cancer Res.2010;70:99-108.
32. Yang R, Cai Z, Zhang Y et al. CD80in immune suppression by mouse ovariancarcinoma-associated Gr-1+CD11b+myeloidcells. Cancer Res.2006;66:6807-15.
33. Fujimura T, Ring S, Umansky V et al. Regulatory T Cells Stimulate B7-H1Expression in Myeloid-Derived Suppressor Cells in ret Melanomas. Invest Dermatol.2011; J doi:10.1038/jid.2011.
34. Mundy-Bosse BL, Lesinski GB, Jaime-Ramirez AC et al. Myeloid-derived suppressorcell inhibition of the IFN response in tumor-bearing mice. Cancer Res.2011;71:5101-10.
35. Fujita M, Kohanbash G, Fellows-Mayle W et al. COX-2blockade suppressesgliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res.2011;71:2664-74.
36. Obermajer N,Muthuswamy R,Odunsi K et al. PGE(2)-induced CXCL12productionand CXCR4expression controls the accumulation of human MDSCs in ovariancancer environment. Cancer Res.2011;71:7463-70.
37. Youn JI, Nagaraj S, Collazo M et al. Subsets of myeloid-derived suppressor cells intumor-bearing mice. J Immunol.2008;181:5791-802.
38. Corzo CA, Condamine T, Lu L et al. HIF-1α regulates function and differentiationof myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med.2010;207:2439-53.
39. Xu L, Zhang G, Zhou Y et al. Stimulation of B7-H3(CD276) directs thedifferentiation of human marrow stromal cells to osteoblasts. Immunobiology.2011;216:1311-7.
40. Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion. CurrCancer Drug Targets.2008;8:404-13.
41. Yuan H, Wei X, Zhang G et al. B7-h3over expression in prostate cancer promotestumor cell progression. The Journal of Urology.2011;186:1093-9.
42. Liu H, Tekle C, Chen YW, et al. B7-H3silencing increases paclitaxel sensitivity byabrogating Jak2/Stat3phosphorylation. Mol Cancer Ther.2011;10:960-71.
43. Jeannin P, Magistrelli G, Aubry JP et al.Soluble CD86is a costimulatory molecule forhuman T lymphocytes.Immunity.2000;13:303-312.
44. Oaks MK, Hallett KM. Cutting edge: a soluble form of CTLA-4in patients withautoimmune thyroid disease.J Immunol.2000,164:5015-5018.
45. Viallard JF, Solanilla A, Gauthier B et al.Increased soluble and platelet-associatedCD40ligand in essential thrombocythemia and reactive thrombocytosis. Blood.2002;99:2612-2614.
46. Wan B, Nie H, Liu A et al. Aberrant regulation of synovial T cell activation by solublecostimulatory molecules in rheumatoid arthritis. J Immunol.2006;177:8844-8850.
47. Wang Q, Chen Y, Xie F et al. Development of a sandwich ELISA for evaluatingsoluble OX40L(CD252)in human sera of different ages or with Graves'disease.Cytokine.2006;36:23-28.
48. Jung HW, Choi SW, Choi JI et al. Serum concentrations of soluble4-1BB and4-1BBligand correlated with the disease severity in rheumatoid arthritis. Exp MolMed.2003,36:13-22.
49. Watanabe N, Gavrieli M, Sedy JR et al. BTLA is a lymphocyte inhibitory receptorwith similarities to CTLA-4and PD-1. Nat Immunol.,2003,4:670-679.
50. Brandt CS, Baratin M, Yi EC et al. The B7family member B7-H6is a tumor cellligand for the activating natural killer cell receptor NKp30in humans. J Exp Med.2009;206:1495-503.
51. Goodwin RG, Din WS, Davis-Smith T, et al. Molecular cloning of a ligand for theinducible T cell gene4-1BB: a member of an emerging family of cytokines withhomology to tumor necrosis factor. Eur J Immunol.1993;23:2631-41.
52. Alderson MR, Craig AS, Tercsa, WT et al. Molecular and biological characterizationof human4-1bb and its ligand. Eur J Immunol.1994;24:2219-27.
53. Godfrey WR, Fagnoni FF, Harara MA et al. Identification of a human OX-40ligand, acostimulator of CD4+T cells with homology to tumor necrosis factor. J Exp Med.1994;180:757-62.
54. Coyle A, Gutierrez-Ramps J. The expanding B7superfanuly: Increasing complexityin costimulatory signals regulating T cell function. Nat Immunol.2001;2:203-9.
55. Greenwald RJ, Freeman GJ, Sharpe AH.The B7family revisited.Annu RevImmunol.2005;23:515-48.
56. Ishida Y, Agata Y, Shibahara Ket al.Induced expression of PD-1,a novel member ofthe immunoglobulin gene superfamily,upon programmed cell death. EMBO.1992;11:3887-95.
57. Dong H, Zhu G, Tamada K, Chen L et al. B7.H1, a third member of the B7family,costimulates T-cell proliferation and secretion of interleukin-10. Nat Med.1999;5:1365-9.
58. Latchman Y, Wood CR, Chernova T et al. PD-L2is a second ligand for PD-1andinhibits T cell activation. Nat Immunol.2001;2:261-9.
59. Dong H, Strome SE, Salomao DR et al. Tumor-associated B7-H1promotes T cellapoptosis: a potential mechanism of immune evasion. Nat Med.2002;8:793-800.
60. Wang S, Zhu G, Chapoval AI et al. Costimulation of T cells by B7-H2, a B7-likemolecule that binds ICOS. Blood.2000;96:2808-13.
61. Yoshinaga S K, Whoriskey JS, Khare SD et al. T-cell co-stimulation through B7RP-1and ICOS. Nature.1999;402:827-32.
62. Swallow MM, Wallin JJ, Sha WC et al. B7h, a novel costimulatory homolog of B7.1and B7.2, is induced by TNF-α. Immunity.1999;11:423-32.
63. Hutloff A, Dittrich AM, Beier KC et al. ICOS is an inducible T-cell co-stimulatorstructurally and functionally related to CD28. Nature.1999;397:263-6.
64. Sica GL, Choi IH, Zhu G et al. B7-H4, a molecule of the B7family, negativelyregulates T cell immunity. Immunity.2003;18:849-61.
65. Chapoval AI, Ni J, Lau JS et al. B7-H3: a costimulatory molecule for T cell activationand IFN-γ production. Nat. Immunol.,2001;2:269-74.
66. Prasad DV, Richards S, Mai XM et al. B7S1, a novel B7family member thatnegatively regulates T cell activation. Immunity.2003;18:863-73.
67. Zang X, Loke P, Kim J et al. B7x: a widely expressed B7family member that inhibitsT cell activation. Proc. Natl. Acad. Sci.,2003;100:10388-92.
68. Watts TH.TNF/TNFR family members in costimulation of T cell responses. Annu RevImmunol.2005;23:23-68.
69. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7SYSTEM OF T CELLCOSTIMULATION. Annu. Rev. Immunol.,1996;14:233-258.
70. Chen L. Co-inhibitory molecules of the B7-CD28family in the control of T-cellimmunity. Nat Rev Immunol.2004;4:336-347.
71. Bretscher PA, Coln M.A theory of self and non selfdiscrimination. Science.1970;169:1042-1049.
72. Bretscher PA. A two-step, two-signal model for the primary activation of precursorhelper T cells. Proc. Natl Acad. Sci.,1999,96:185 190.
73. Hodge JW, Greiner JW, Tsang KYet al. Costimulatory molecules as adjuvants forimmunotherapy. Front Biosci.2006;11:788-803.
74. Greenwald RJ, Freeman GJ, Sharpe AH.The B7family revisited.Annu Rev Immunol.2005;23:515-548.
1. A. K. Abbas,“The control of T cell activation vs. tolerance,” Autoimmunity Reviews,vol.2, no.3, pp.115–118,2003.
2. L. Chen, et al.“Co-inhibitory molecules of the B7-CD28family in the control of T-cellimmunity,” Nature Reviews Immunology, vol.4, no.5, pp.336–347,2004.
3. R. J. Greenwald, G. J. Freeman, and A. H. Sharpe,“The B7family revisited,” AnnualReview of Immunology, vol.23, pp.515–548,2005.
4. M. Loos, N. A. Giese, and N. A. Giese,“Clinical significance and regulation of thecostimulatory molecule B7-H1in pancreatic cancer,” Cancer Letters, vol.268, no.1,pp.98–109,2008.
5. J. Konishi, K. Yamazaki, M. Azuma, I. Kinoshita, H. Dosaka-Akita, and M. Nishimura,“B7-H1expression on non-small cell lung cancer cells and its relationship withtumor-infiltrating lymphocytes and their PD-1expression,” Clinical Cancer Research,vol.10, no.15, pp.5094–5100,2004.
6. Y. Liu, B. Zeng, Z. Zhang, Y. Zhang, and R. Yang,“B7-H1on myeloid-derivedsuppressor cells in immune suppression by a mouse model of ovarian cancer,” ClinicalImmunology, vol.129, no.3, pp.471–481,2008.
7. H. Ghebeh, S. Mohammed, and S. Mohammed,“The B7-H1(PD-L1) Tlymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltratingductal carcinoma: correlation with important high-risk prognostic factors,” Neoplasia,vol.8, no.3, pp.190–198,2006.
8. R.H.Thompson, M. D. Gillett, and M. D. Gillett,“Costimulatory B7-H1in renal cellcarcinoma patients: indicator of tumor aggressiveness and potential therapeutic target,”Proceedings of the National Academy of Sciences of the United States of America, vol.101, no.49, pp.17174–17179,2004.
9. E. J. Small, N. S. Tchekmedyian, B. I. Rini, L. Fong, I. Lowy, and J. P. Allison,“Apilot trial of CTLA-4blockade with human anti-CTLA-4in patients withhormone-refractory prostate cancer,” Clinical Cancer Research, vol.13, no.6, pp.1810–1815,2007.
10. E. D. Kwon, B. A. Foster, A. A. Hurwitz, C. Madias, J. P. Allison, N. M. Greenberg,and M. B. Burg,“Elimination of residual metastatic prostate cancer after surgery andadjunctive cytotoxic T lymphocyte-associated antigen4(CTLA-4) blockadeimmunotherapy,” Proceedings of the National Academy of Sciences of the UnitedStates of America, vol.96, no.26, pp.15074–15079,1999.
11. M. R. Theoret, P. M. Arlen, M. Pazdur, W. L. Dahut, J. Schlom, and J. L. Gulley,“Phase I trial of an enhanced prostate-specific antigen-based vaccine and anti-CTLA-4antibody in patients with metastatic androgen-independent prostate cancer,” ClinicalGenitourinary Cancer, vol.5, no.5, pp.347–350,2007.
12. C. I. Liakou, A. Kamat, and A. Kamat,“CTLA-4blockade increases IFNγ-producingCD4+ICOS hi cells to shift the ratio of effector to regulatory T cells in cancerpatients,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.105, no.39, pp.14987–14992,2008.
13. R. H. Thompson, J. P. Allison, and E. D. Kwon,“Anti-cytotoxic T lymphocyteantigen-4(CTLA-4) immunotherapy for the treatment of prostate cancer,” UrologicOncology, vol.24, no.5, pp.442–447,2006.
14. J. A. Blansfield, K. E. Beck, and K. E. Beck,“Cytotoxic T-lymphocyte-associatedantigen-4blockage can induce autoimmune hypophysitis in patients with metastaticmelanoma and renal cancer,” Journal of Immunotherapy, vol.28, no.6, pp.593–598,2005.
15. J. Yuan, S. Gnjatic, and S. Gnjatic,“CTLA-4blockade enhances polyfunctionalNY-ESO-1specific T cell responses in metastatic melanoma patients with clinicalbenefit,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.105, no.51, pp.20410–20415,2008.
16. D. O'Mahony, J. C. Morris, and J. C. Morris,“A pilot study of CTLA-4blockade aftercancer vaccine failure in patients with advanced malignancy,” Clinical CancerResearch, vol.13, no.3, pp.958–964,2007.
17. S. M. Ansell, S. A. Hurvitz, and S. A. Hurvitz,“Phase I study of ipilimumab, ananti-CTLA-4monoclonal antibody, in patients with relapsed and refractory B-cellnon-Hodgkin lymphoma,” Clinical Cancer Research, vol.15, no.20, pp.6446–6453,2009.
18. A.I. Chapoval, J. Ni, and J. Ni,“B7-H3: a costimulatory molecule for T cell activationand IFN-γ production,” Nature Immunology, vol.2, no.3, pp.269–274,2001.
19. R. Castriconi, A. Dondero, and A. Dondero,“Identification of4Ig-B7-H3as aneuroblastoma-associated molecule that exerts a protective role from an NKcell-mediated lysis,” Proceedings of the National Academy of Sciences of the UnitedStates of America, vol.101, no.34, pp.12640–12645,2004.
20. P. Steinberger, O. Majdic, and O. Majdic,“Molecular characterization of human4Ig-B7-H3, a member of the B7family with four Ig-like domains,” Journal ofImmunology, vol.172, no.4, pp.2352–2359,2004.
21. M. Hashiguchi, H. Kobori, P. Ritprajak, Y. Kamimura, H. Kozono, and M. Azuma,“Triggering receptor expressed on myeloid cell-like transcript2(TLT-2) is acounter-receptor for B7-H3and enhances T cell responses,” Proceedings of theNational Academy of Sciences of the United States of America, vol.105, no.30, pp.10495–10500,2008.
22. J. Klesney-Tait, I. R. Turnbull, and M. Colonna,“The TREM receptor family andsignal integration,” Nature Immunology, vol.7, no.12, pp.1266–1273,2006.
23. J. Leitner, C. Klauser, and C. Klauser,“B7-H3is a potent inhibitor of human T-cellactivation: no evidence for B7-H3and TREML2interaction,” European Journal ofImmunology, vol.39, no.7, pp.1754–1764,2009.
24. Y. Sun, Y. Wang, J. Zhao, M. Gu, R. Giscombe, A. K. Lefvert, and X. Wang,“B7-H3and B7-H4expression in non-small-cell lung cancer,” Lung Cancer, vol.53, no.2, pp.143–151,2006.
25. M. Loos, D. M. Hedderich, and D. M. Hedderich,“Expression of the costimulatorymolecule B7-H3is associated with prolonged survival in human pancreatic cancer,”BMC Cancer, vol.9, article463,2009.
26. X.-P. Wu, J.-T. Jiang, and J.-T. Jiang,“Relationship between co-stimulatory molecueB7-H3expression and gastric carcinoma histology and prognosis,” World Journal ofGastroenterology, vol.12, no.3, pp.457–459,2006.
27. X. Zang, P. S. Sullivan, and P. S. Sullivan,“Tumor associated endothelial expressionof B7-H3predicts survival in ovarian carcinomas,” Modern Pathology, vol.23, no.8,pp.1104–1112,2010.
28. P. L. Crispen, Y. Sheinin, and Y. Sheinin,“Tumor cell and tumor vasculatureexpression of B7-H3predict survival in clear cell renal cell carcinoma,” ClinicalCancer Research, vol.14, no.16, pp.5150–5157,2008.
29. J. Sun, L.-J. Chen, and L.-J. Chen,“Clinical significance and regulation of thecostimulatory molecule B7-H3in human colorectal carcinoma,” Cancer Immunology,Immunotherapy, vol.59, no.8, pp.1163–1171,2010.
30. S. A. Boorjian, Y. Sheinin, and Y. Sheinin,“T-Cell coregulatory molecule expressionin urothelial cell carcinoma: clinicopathologic correlations and association withsurvival,” Clinical Cancer Research, vol.14, no.15, pp.4800–4808,2008.
31. T. J. Roth, Y. Sheinin, and Y. Sheinin,“B7-H3ligand expression by prostate cancer: anovel marker of prognosis and potential target for therapy,” Cancer Research, vol.67,no.16, pp.7893–7900,2007.
32. L. Wang, C. C. Fraser, and C. C. Fraser,“B7-H3promotes acute and chronic allograftrejection,” European Journal of Immunology, vol.35, no.2, pp.428–438,2005.
33. Nagashima, N. Harada, and N. Harada,“B7-H3contributes to the development ofpathogenic Th2cells in a murine model of asthma,” Journal of Immunology, vol.181,no.6, pp.4062–4071,2008.
34. L. Luo, A. I. Chapoval, and A. I. Chapoval,“B7-H3enhances tumor immunity in vivoby costimulating rapid clonal expansion of antigen-specific CD8+cytolytic T cells,”Journal of Immunology, vol.173, no.9, pp.5445–5450,2004.
35. X. Sun, M. Vale, E. Leung, J. R. Kanwar, R. Gupta, and G. W. Krissansen,“MouseB7-H3induces antitumor immunity,” Gene Therapy, vol.10, no.20, pp.1728–1734,2003.
36. C. M. Lupu, C. Eisenbach, A. D. Lupu, M. A. Kuefner, B. Hoyler, W. Stremmel, and J.Encke,“Adenoviral B7-H3therapy induces tumor specific immune responses andreduces secondary metastasis in a murine model of colon cancer,” Oncology reports,vol.18, no.3, pp.745–748,2007.
37. L. Ma, L. Luo, and L. Luo,“Complete eradication of hepatocellular carcinomas bycombined vasostatin gene therapy and B7H3-mediated immunotherapy,” Journal ofHepatology, vol.46, no.1, pp.98–106,2007.
38. W.-K. Suh, B. U. Gajewska, and B. U. Gajewska,“The B7family member B7-H3preferentially down-regulates T helper type1-mediated immune responses,” NatureImmunology, vol.4, no.9, pp.899–906,2003.
39. D. V. R. Prasad, T. Nguyen, Z. Li, Y. Yang, J. Duong, Y. Wang, and C. Dong,“MurineB7-H3is a negative regulator of T cells,” Journal of Immunology, vol.173, no.4, pp.2500–2506,2004.
40. A.Fukushima, T.Sumi, and T. Sumi,“B7-H3regulates the development ofexperimental allergic conjunctivitis in mice,” Immunology Letters, vol.113, no.1, pp.52–57,2007.
41. K. Mahnke, S. Ring, and S. Ring,“Induction of immunosuppressive functions ofdendritic cells in vivo by CD4+CD25+regulatory T cells: role of B7-H3expressionand antigen presentation,” European Journal of Immunology, vol.37, no.8, pp.2117–2126,2007.
42. G. Zhang, Y. Xu, X. Lu, H. Huang, Y. Zhou, B. Lu, and X. Zhang,“Diagnosis value ofserum B7-H3expression in non-small cell lung cancer,” Lung Cancer, vol.66, no.2,pp.245–249,2009.
43. X. Zang, R. H. Thompson, and R. H. Thompson,“B7-H3and B7x are highlyexpressed in human prostate cancer and associated with disease spread and pooroutcome,” Proceedings of the National Academy of Sciences of the United States ofAmerica, vol.104, no.49, pp.19458–19463,2007.
44. S. A. Boorjian, Y. Sheinin, P. L. Crispen, C. M. Lohse, B. C. Leibovich, and E. D.Kwon,“T-cell co-regulatory molecule expression in renal angiomyolipoma andpulmonary lymphangioleiomyomatosis,” Urology, vol.74, no.6, pp.1359–1364,2009.
45. Gregorio, M. V. Corrias, and M. V. Corrias,“Small round blue cell tumours: diagnosticand prognostic usefulness of the expression of B7-H3surface molecule,”Histopathology, vol.53, no.1, pp.73–80,2008.
46. S. Parker, M. G. Heckman, and M. G. Heckman,“Evaluation of B7-H3expression as abiomarker of biochemical recurrence after salvage radiation therapy for recurrentprostate cancer,” International Journal of Radiation Oncology, Biology, Physics. Inpress.
47. Yamato, M. Sho, and M. Sho,“Clinical importance of B7-H3expression in humanpancreatic cancer,” British Journal of Cancer, vol.101, no.10, pp.1709–1716,2009.
48. Tirapu, E. Huarte, and E. Huarte,“Low surface expression of B7-1(CD80) is animmunoescape mechanism of colon carcinoma,” Cancer Research, vol.66, no.4, pp.2442–2450,2006.
49. K. H. Yi and L. Chen,“Fine tuning the immune response through B7-H3and B7-H4,”Immunological Reviews, vol.229, no.1, pp.145–151,2009.
50. T. Sun, Z. Hu, H. Shen, and D. Lin,“Genetic polymorphisms in cytotoxicT-lymphocyte antigen4and cancer: the dialectical nature of subtle human immunedysregulation,” Cancer Research, vol.69, no.15, pp.6011–6014,2009.
51. Chen YW, Tekle C, Fodstad O. The immunoregulatory protein human B7H3is atumor-associated antigen that regulates tumor cell migration and invasion. Curr CancerDrug Targets.2008;8:404-13.
52. Yuan H, Wei X, Zhang G et al. B7-h3over expression in prostate cancer promotestumor cell progression. The Journal of Urology.2011;186:1093-9.
53. Xu L, Zhang G, Zhou Y et al. Stimulation of B7-H3(CD276) directs thedifferentiation of human marrow stromal cells to osteoblasts. Immunobiology.2011;216:1311-7.
54. Liu H, Tekle C, Chen YW, et al. B7-H3silencing increases paclitaxel sensitivity byabrogating Jak2/Stat3phosphorylation. Mol Cancer Ther.2011;10:960-71
55. M. Z. Dewan, A. E. Galloway, N. Kawashima, J. K. Dewyngaert, J. S. Babb, S. C.Formenti, and S. Demaria,“Fractionated but not single-dose radiotherapy induces animmune-mediated abscopal effect when combined with anti-CTLA-4antibody,”Clinical Cancer Research, vol.15, no.17, pp.5379–5388,2009.
56. A.V. Maker, G. Q. Phan, and G. Q. Phan,“Tumor regression and autoimmunity inpatients treated with cytotoxic T lymphocyte-associated antigen4blockade andinterleukin2: a phase I/II study,” Annals of Surgical Oncology, vol.12, no.12, pp.1005–1016,2005.
57. F. S. Hodi, M. C. Mihm, and M. C. Mihm,“Biologic activity of cytotoxic Tlymphocyte-associated antigen4antibody blockade in previously vaccinatedmetastatic melanoma and ovarian carcinoma patients,” Proceedings of the NationalAcademy of Sciences of the United States of America, vol.100, no.8, pp.4712–4717,2003.
58. H. J. J. van der Vliet, H. B. Koon, and H. B. Koon,“Effects of the administration ofhigh-dose interleukin-2on immunoregulatory cell subsets in patients with advancedmelanoma and renal cell cancer,” Clinical Cancer Research, vol.13, no.7, pp.2100–2108,2007.
59. J. R. Brahmer, C. G. Drake, and C. G. Drake,“Phase I study of single-agentanti-programmed death-1(MDX-1106) in refractory solid tumors: safety, clinicalactivity, pharmacodynamics, and immunologic correlates,” Journal of ClinicalOncology, vol.28, no.19, pp.3167–3175,2010.