调控骨肉瘤细胞表面Tn/T抗原转化增强机体抗肿瘤免疫能力的研究

Osteosarcoma is the most prevalent bone neoplasm among the malignancies in adolescence and has become a major threaten for teenagers' health. In current clinical practice, surgery is still the essential treatment, sometimes combined with adjuvant radiochemotherapy. However, the prognostic of these patients remains far from satisfactory. Thus, development of a more effective approach to treat osteosarcoma has become very urgent and of great importance. Tn antigen and T antigen have been reported as tumor markers served in the neoplasms diagnosis and their levels are closely correlated with disease progression. Tn antigen, the precursor of T antigen, is transformed to T antigen by T antigen-synthase. In addition, it has been demonstrated that high level of T antigen-expression rather than that of Tn antigen is predictor of a better outcome. Moreover, our previous study showed that enhanced expression of T antigen-synthase in tumor cells resulted in significant proliferation and reduced apoptosis of tumor-specific CD8+ T cells in vitro. All the data suggest that T antigen-synthase might play a critical role in malignant pathogenesis. Accordingly, our study is aimed to up-regulate the transformation of Tn antigen to T antigen by enhanced expression of T antigen-synthase. Then we observe the effect of this change to the biological behavior of osteosarcoma cells and to tumor-specific immunity. Furthermore, we will try to elucidate the potential mechanism.

骨肉瘤是一种在青少年恶性肿瘤中发病率居首位的骨肿瘤，严重危害青少年健康，目前其临床治疗以手术治疗为主，辅以放化疗，但治疗效果并不理想，寻找新的骨肉瘤诊疗方法对保护青少年健康具有重要意义。Tn抗原（即黏蛋白型O-聚糖 GalNAcα1-S/T）与T抗原作为肿瘤标志物之一，与肿瘤的诊断及预后密切相关，Tn抗原是合成T抗原的前体，Tn抗原在T抗原合成酶的作用下形成T抗原。有研究表明T抗原高表达的肿瘤患者预后较Tn抗原高表达者为佳。我们前期研究发现高表达T 抗原合成酶的肿瘤细胞体外能增强肿瘤特异性CD8+细胞增殖，减少CD8+T细胞凋亡。本课题综合已有的研究数据，拟通过上调骨肉瘤细胞中T抗原合成酶的表达水平，促使骨肉瘤细胞中更多的Tn抗原转变为T抗原，观察此种改变对骨肉瘤细胞生物学行为及机体肿瘤免疫能力的影响，并探寻其可能的作用机制，以期为骨肉瘤的治疗提供一个新的靶标。

骨肉瘤是一种在青少年恶性肿瘤中发病率居首位的骨肿瘤，严重危害青少年健康，目前其临床治疗以手术治疗为主，辅以放化疗，但治疗效果并不理想，寻找新的骨肉瘤诊疗方法对保护青少年健康具有重要意义。本研究通过提高骨肉瘤细胞中T抗原合成酶的表达水平上调骨肉瘤细胞表面T抗原表达水平，发现高表达T抗原的骨肉瘤细胞体外增殖能力增强，但其体内生长能力受限，进一步研究发现高表达T抗原的骨肉瘤细胞免疫原性增强，在体内和体外均能够增强CD8+T细胞增殖能力，降低CD8+T细胞凋亡水平，提高细胞毒性T细胞的肿瘤杀伤能力。高表达T抗原的骨肉瘤细胞体内能够刺激脾脏细胞分泌更多的抗肿瘤细胞因子INF-gamma与TNF-alpha，同时脾脏中分泌IFN-gamma的CD4+T细胞比对照组显著增多。在免疫保护试验中，经过高表达T抗原的灭活骨肉瘤细胞免疫过的小鼠荷瘤时，其体内骨肉瘤细胞的生长较对照组明显受到抑制。以上研究结果表明高表达T抗原的骨肉瘤细胞具有很强的免疫原性，具有制备新型肿瘤细胞疫苗的应用潜力。本研究为骨肉瘤的免疫治疗提供了一种新的思路。