肿瘤相关抗原ROR1的分子修饰及其作用机制研究

Breast cancer is a serious threaten to the health of women. With the development of molecular biology, cell biology and immunology research, immunotherapy has become a promising therapy for breast cancer patients. TLRs is a bridge linked innate immunity and acquired immunity, TLRs agonists can activate immune protection. Our previous studies have found that ROR1 was a tumor associated antigen, could be used as a tumor specific target for the treatment of breast cancer. In this project, ROR1 is coupled with TLR9 agonist thymosin alpha 1 to generate a novel tumor antigen T alpha 1 - ROR1. Xenograft model of breast cancer is established to induce the anti-tumor natural immunity and acquired immunity and the mechanism is studied; furthermore, the model of lung metastasis of breast cancer and SCID mice adoptive therapy are established to study the role of T alpha1-ROR1 in inducing memory T cells to prevent relapse and metastasis,thus to provide a new method for breast cancer vaccine.

乳腺癌是一种严重威胁妇女健康的恶性肿瘤。随着分子生物学、细胞生物学和免疫学等研究的进展，免疫治疗作为一种极具发展前景的治疗方式成为乳腺癌患者重要而有效的辅助治疗。TLRs是联系天然免疫与获得性免疫之间的桥梁，TLRs激动剂可通过激活免疫细胞参与机体的免疫保护。我们前期研究发现ROR1是一个乳腺癌肿瘤相关抗原，可以作为肿瘤特异靶点用于治疗。本课题将ROR1抗原肽与TLR9小分子激动剂胸腺肽α1化学偶联产生新型肿瘤抗原Tα1- ROR1，建立小鼠乳腺癌移植瘤模型，研究其诱导机体抗肿瘤天然免疫和获得性免疫应答的能力及其机制；进一步建立乳腺癌肺转移及SCID鼠过继治疗模型，研究Tα1- ROR1诱导机体产生记忆T细胞预防复发转移的能力及其机制，从而为研制乳腺癌新型疫苗奠定基础。

乳腺癌是一种严重威胁妇女健康的恶性肿瘤。随着分子生物学、细胞生物学和免疫学等研究的进展，免疫治疗作为一种极具发展前景的治疗方式成为乳腺癌患者重要而有效的辅助治疗。TLRs 是联系天然免疫与获得性免疫之间的桥梁，TLRs 激动剂可通过激活免疫细胞参与机体的免疫保护。我们前期研究发现ROR1 是一个乳腺癌肿瘤相关抗原，可以作为肿瘤特异靶点用于治疗。本研究采用生物信息学并结合实验技术首次从小鼠ROR1全长氨基酸序列中筛选出1条受H-2Kd限制的CTL表位，用胸腺肽α1 共价化学偶联ROR1制备肿瘤抗原Tα1-ROR1，在体外证实其具有生物学活性，能诱导小鼠脾淋巴细胞分泌IFN-γ和IL-12。体内实验表明Tα1-ROR1能抑制肿瘤生长，对荷瘤小鼠具有明显的免疫保护作用。为进一步研究其抗肿瘤免疫应答的能力及其机制及研制乳腺癌新型疫苗奠定了基础。