【作者】 张浩；

【导师】 郑树森；

【作者基本信息】 浙江大学 ， 外科学， 2005， 博士

【摘要】 原发性肝癌(HCC hepatocellular carcinoma)是我国最常见的恶性肿瘤之一,不但发病率及病死率极高,而且治疗困难,预后极差。目前肝癌的治疗主要采用以手术治疗为主的综合治疗方案。虽然医学影像技术的快速发展、外科手术技术及围手术期管理水平的不断提高、肝移植临床逐步推广应用以及不能切除肝癌的缩小后切除使肝癌的早期诊断率及手术切除率有了明显的提高,但术后较高的复发及转移率是影响手术治疗中、远期效果的主要原因。迄今为止肝癌的复发及转移仍无有效的预防和治疗方法,如何进一步深化肝癌生物学特性研究,积极寻找有效的预防和治疗肝癌复发和转移的措施是肝癌研究的一个重要目标。在现代分子生物学和基因工程技术飞速发展的推动下,以免疫治疗为基础发展而来的生物治疗日益受到重视,显示良好的应用前景,可望成为除手术、放疗和化疗这三大治疗模式之外的肝癌治疗第四模式。 研究表明,树突状细胞(DC dendritic cell)是目前已知最强有力的专职抗原提呈细胞,不但表达丰富的MHC(MHC major histocompatibility complex)Ⅰ、Ⅱ类分子、共刺激分子及粘附分子,而且高水平分泌IL-1(interleulin-1),TNF-α(tumor necrosis factor-α),IL-12等细胞因子,启动T细胞介导的免疫应答特别是杀伤性T淋巴细胞(CTL cytotoxic Tlymphocyte)介导的免疫反应,在机体抗肿瘤免疫中发挥重要作用。以肿瘤抗原体外致敏DC,使之持续高水平表达肿瘤抗原表位,然后将负载有肿瘤抗原的致敏DC回输至荷瘤机体,通过MHC Ⅰ、Ⅱ类分子途径交叉递呈抗原,以有效地诱导机体产生特异及非特异性的抗肿瘤免疫应答,是目前肿瘤治疗的一条有效途径。随着体外大量培养DC方法的成熟,以DC为基础的抗肿瘤疫苗正成为研究的热点。目前对DC进行处理,使其表达肿瘤抗原的常用方法有:肿瘤特异性抗原基因修饰,肿瘤抗原肽或粗提物冲击,肿瘤DNA或mRNA冲击。虽然在动物及临床试验中取得了一定的治疗效果,但由于目前明确鉴定的肿瘤特异性抗原数量较少,抗原肽及核酸冲击的稳定性差、表达时间短以及致自身免疫性疾病可能等限制了上述方法的临床应用。因此,如何进一步研究加强机体抗肿瘤免疫更多还原

【Abstract】 Lymphotactin enhances the antitumor efficacy of dendritoma formed bydendritic cells and mouse hepatocellular carcinoma cellsDepartment of Hepatobiliary Pancreatic Surgery. Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, College of Medicine,Zhejiang University, ChinaM.D Student: Zhang HaoSupervisor: Pro. Zheng Shu-senHepatocellular carcinoma (HCC) is one of the most common malignances in our country. The incidence and mortality rates are high, the treatment is challenging, and the prognosis is still poor. Now the treatment option is multimodality therapy in which surgical resection plays the most important role. But the high incidence of recurrence and metastases remains a critical issue other than the improvements in radiological diagnosis, surgical techniques, perioperative management and the availability of downstaging resection and liver transplantation which all have contributed to increase the resectability rates, we still lack of definitive method to prevent and treat recurrences and metastases of HCC. So it is the key role to find a novel method to overcome this obstacle. Following the quick development of modern molecular biology and gene engineering. Biotherapies based on the development of immunology showed promising results, and gained popular recognition. As we attain a deeper understanding of the characteristics of HCC, we may be more powerful to exploit the biofeature and immune response of HCC and use it as a platform on which to build a successful therapeutic strategy to fight cancer. The increasing knowledge of the mechanisms involved in immune reactions against cancer cells has lead to the development of experimental and clinical immunotherapeutic approaches for the treatment of cancer patients and the prevention of cancer recurrence. Biotherapies recently attracting much more attention and would probably be the forth therapy model except operation, radiation and chemotherapy.Dendritic cell (DC) is the most potent antigen-presenting cell at present, which play a key role in the initiation of immune response. These cells are considered promising tools and targets for immunotherapy. They possess an extraordinary capacity to capture and processantigen and contain all that is needed to stimulate T cell immunity, including high level of major histocompatibility complex, costimulatory molecules, and adhesion molecules as well as a variety of immunologically important cytokines such as IL-1. TNF-a, and IL-12. These properties, coupled with the fact that it is now possible to generate, ex vivo, large numbers of functional DCs from a patient’s peripheral blood monocytes or CD34 haemopoietic stem cells, have led to considerable interest in the use of dendritic cell vaccines as a means to induce antitumour immunity. There were different strategies that had been applied in animal experiments or clinical trials to deliver antigen to DC. such as pulsing synthetic or eluted peptides, transfection with cDNA or RNA encoding known TAA, loading tumor lysate or tumor RNA. However, these approaches are currently limited for clinical application, as few human tumor rejection antigens have been identified. The high polymorphism of the human HLA system has also made it difficult to identify tumor-associated peptides as a vaccine for cancer therapy. In addition, using tumor lysate or DNA/RNA loading method creates the risk of inducing immune responses against numerous self-antigens shared with normal cells.Gong et al first used bone marrow derived DCs as fusion partners for tumor cells in 1997, which broadened the vision of the vaccine research. Kugler et al generated hybrids of autologous tumor cells and allogeneic DCs using electrofusion techniques in 2000, which showed that the hybrid cell vaccination was a safe and effective immune therapy for human metastatic renal cell carcinoma. These promoted the possibility of treatment common human tumours with dendritoma. To date there has seldom reported research on DC fusion immunotherapy for HCC, and has no related resea更多还原