实体肿瘤固有CD96通过调控肿瘤干细胞促进化疗耐药的机制探讨

CD96是一个新的免疫抑制受体，虽然它在白血病干细胞中表达并降低患者的生存率，但其具体机制和在实体瘤中的作用仍不清楚。申请人前期揭示了乳腺癌干细胞促进乳腺癌的耐药和远处转移，成果以通讯或共同作者身份发表在Cancer Gene Therapy和Advanced Science杂志。在本项目中，申请人前期发现乳腺癌细胞固有CD96促进患者的化疗耐药，与乳腺癌患者的生存和预后呈负相关关系，它的功能阻断明显抑制乳腺癌干细胞的成球能力和干性标记物表达，并促进STAT3的活性抑制和化疗药物对乳腺癌干细胞的杀伤。在此基础上，本课题拟使用蛋白组学、CO-IP和PDX (patient-derived xenograft)等技术进一步探索CD96调控乳腺癌干细胞耐药的具体机制。本研究将阐明免疫抑制性受体在实体肿瘤治疗中的新机制以及为肿瘤干细胞耐药的治疗提供新的思路。

CD96 is a new immunosuppressive receptor. Although CD96 is expressed in leukemia stem cells and reduces the survival of patients, its specific mechanism and role in solid tumors remain unknown. We revealed the breast cancer stem cells enhances chemoresistance and metastasis in previous work, and the results were published in Cancer Gene Therapy and Advanced Science as corresponding author or co-author. In this project, we have discovered that intrinsic-CD96 in breast cancer cells promotes chemoresistance and negatively correlates with survival and prognosis of breast cancer patients. The intervention of CD96 function inhibited the sphere forming ability and expression of cancer stem cell marker of breast cancer stem cell and promoted the inhibition of STAT3 activity and chemotherapy efficacy. On this basis, the study intends to further explore the specific mechanism of CD96 in the regulation of chemoresistance of breast cancer stem cells using proteomic, CO-IP, PDX (patient-derived xenograft), and so on. This study will clarify the new mechanism of immunosuppressive receptors in anti-tumor therapy and provide a new pathway for the therapy of chemoresistance in cancer stem cells.