Induction Of Specific Antitumor Immune Responses By Vaccination With Dendritic Cells Pulsed With Lung Cancer Cell Lysates

In 1996,report by WHO, Lung cancer is the first cause of cancer death in the world. In2001,it was estimated that cancer of the lung and bronchus would account for 25% of allcancer deaths and 13% of new cases. In 1998 a malignant tumor epidemic survey in shanghaiindicates that the incidence of lung cancer among man and woman have reached to52.6/100,000 and 18.2/100,000 respectively, and have taken the first place and the third placein all the epidemic incidences. So lung cancer remains a significant health concern in theworld despite several decades of research in both prevention and treatment. Conventionaltreatment for lung cancer includes surgery, chemotherapy, and radiation therapy used aloneor in combination. Despite the increasingly intense application and continuous modificationof these approaches, the overall cure rate for lung cancer remains poor, especially for patientswith advanced disease. Thus, the need to explore new treatment options is paramount. In the area of treatment for tumor, with all the progress made in immunotherapy duringthe past 40 years, it has not been established as a substitute for conventional therapy fortumor, which is largely due to lack of knowledge of "oncology immunotherapy". Recentclinical studies have shown that immunotherapeutics with DC-based cancer vaccines have thepotential to improve patient outcome for a wide range of tumor types, including melanoma,B-cell lymphoma, multiple myeloma, fibro sarcoma, kidney cancer and prostate cancer. DCare potent antigen-presenting cells uniquely capable of inducing both primary and recallimmune responses, and they are key to stimulating clinically meaningful antitumor immunity.Increasing evidence has demonstrated that DC, when loaded with tumor antigens, are able toprocess the loaded antigens and present antigenic epitopes to T cells, resulting in theinduction of tumor-specific CTL and antitumor immunity. To date, many methods have beendeveloped or evaluated for loading tumor antigens to DC. The choice of method is largely 第 7 页第二军医大学硕士学位论文 英文摘要 胸心外科专业dependent on the type of DC vaccine to be developed, the availability of defined tumorantigens or antigenic peptide epitopes and the supply of tumor materials. For those tumortypes for which no defined tumor-specific antigens are available, such as lung cancer, loadingDC with whole tumor cells is a practical choice. It has been shown that dendritic cells canefficiently phagocytosis various forms of tumor cells, including live, apoptotic and necrotictumor cells and acquire tumor antigens from the phagocytosis tumor cells. Human DC loadedwith tumor cells derived from either fresh tumor tissues or established tumor cell lines haveinduced tumor-specific CTL in vitro for many cancers. In mouse models, CTL induction andprotective antitumor immunity with tumor cell-loaded DC were also demonstrated in vivo.To date, limited studies have addressed the use of this approach for lung cancer. This report,basis in domestic and board study, throught in vitro and in vivo reaching, we assessed thefeasibility of developing a DC-based vaccine for the treatment of lung cancer. Using tumorcell freeze-thaw lysates as a tumor antigen, we demonstrated the efficiency of DC inacquiring and presenting antigenic epitopes derived from the lung tumor cell lysates. Theresults provide insight into the development of alternative strategies for treatment of lungcancer and extend the repertoire of tumor types that may be suitable for the development ofDC-based cancer vaccines. Methods 1.Peripheral blood monocyte-derived DCs isolation; culture and identification. PBMC(Peripheral blood mononuclear cells) were isolated from the Peripheral blood ofhealthy HLA-A2+donors by density gradient centrifugation.Briefly,PBMC were incubated intissue culture flasks overnight in 5%CO2 at 37℃ in RPMI 1640 medium sup...