同种异基因造血干细胞移植后急性移植物抗宿主病对肝癌细胞生长、转移的影响及相关机制研究

The role of immune system in recognizing and killing malignant cells has been focused for a long time. At present, it is the main strategy in which autologous tumor-killing lymphocytes are activated and proliferate in vitro, and then infused back to patients. However, the limited tumor killing effect of autologous lymphocytes is observed in clinical application. It is necessary to explore new immunological approach. Graft-versus-host disease (GVHD) is a phenomenon almost unique to allogeneic bone marrow transplantation whereby lymphocytes are introduced and permitted to engraft and proliferate within an immunocompromised host. At the same time of damage to normal tissue, GVHD eradicates residual host malignant cells through immunologic mechanisms and reduces the relapse of leukemia. It has been recognized that allogeneic lymphocyte may be a valuable approach in treatment of cancers beyond hematological malignancies. But there are few researches in this field. Since the previous studies on the effect of GVHD on hematological malignancies, we plan to investigate the effect and mechanism of GVHD on hepatocellular carcinoma (HCC). First, GVHD is induced in C57BL/6 mice through different methods, by which we try to regulate the severity of GVHD in the beginning; Second, we construct the murine model with implanted HCC and then induce different levels of GVHD in these models, to investigate the effect of GVHD on the growth, metastasis of HCC; and last, the tumor microenvironment, effector lymphocytes, cytokines, chemokine and cell surface markers will be tested and estimated to investigate the mechanism of the interaction between the GVHD and HCC. The results of this study will provide evidence for the application of GVHD in the treatment of solid tumors.

利用免疫系统识别、杀伤肿瘤是当前研究的热点。但目前采用患者自身免疫细胞在体外激活、增殖并回输入体内的治疗方法效果有限。移植物抗宿主病（GVHD）是器官移植后外来移植物的淋巴细胞识别受体抗原所致的排斥反应。已有的研究证实，造血干细胞移植后轻-中度GVHD可以杀伤各种血液肿瘤细胞，起到有效的治疗作用。提示外源性的淋巴细胞在肿瘤的治疗领域有着广阔的应用前景。但目前对于实体肿瘤的治疗方面系统研究报道较少。在此基础上，本课题拟利用不同的造血干细胞移植方案，研究初始诱发阶段急性GVHD程度的可控性；在裸鼠荷瘤模型上，通过诱发不同程度的急性GVHD，观察肝癌生长、转移的不同状态，研究急性GVHD对实体肿瘤的杀伤作用；并通过检测肿瘤周边微环境、效应免疫细胞、细胞因子、趋化因子、细胞表面标记等，研究GVHD与肝癌之间的作用机制。为未来GVHD用于实体肿瘤的全身治疗提供新思路。