ABO天然抗原抗体系统在三阴乳腺癌基因免疫治疗中应用的基础研究

Of all types of breast cancer, triple-negative breast cancer (TNBC) is characterised by high early recurrence and metastasis rate and poor prognosis， and with a poor response to routine therapies. Patients of TNBC can’t benefit from endocrinology or targeted therapy due to lack of corresponding targets. So it has become a challenge or a problem in clinical treatments. Combination of suicide gene therapy and immunotherapy brings hope to triple negative breast cancer. Human ABO blood antigen-antibody system is a kind of inherent immune system. .Studies have shown that breast cancer cells highly express the precursors of blood group antigen H, which could be converted into blood group antigen A or B by glycosylation of BGA glycosyltransferase. The change in the expression of blood group antigens (BGA) is associated with malignancy, which can affect the proliferation, differentiation and metastasis abilities. Meanwhile, BGA are a group of allo-antigens with strong immunogenicity and antigenicity, which could be identified by blood group antibodies and activate complement-dependent cytotoxicity(CDC) and antibody-dependent cell-mediated cytoxicity(ADCC) such as the hemolytic reaction. It is unclear that whether we could target BGA as a therapeutic target for TNBC treatment..From the previous results of our research group, we established the blood group antigen A highly expressed MDA-MB-231 cell line. Then verified the negative regulation function of BGA on tumor cells after blood group antigen A transfection. Meanwhile, the anti-tumor effect of type B plasma via CDC and ADCC effect were verified. Type B plasma also induced immunogenic cell death. For further research on the practicability of ABO blood group antigen act as a potential target, we plan to do more researches on the anti-tumor effect in vivo via establishment of mouse model. This will provide more fundamental basis for the application of inherent BGA system and gene therapy as a potential therapy for triple negative breast cancer.

三阴乳腺癌早期复发转移率高、预后差，对常规治疗反应不佳，因缺乏相应靶点也无法从靶向治疗及内分泌治疗中获益，是临床治疗的难点。自杀基因疗法与肿瘤免疫疗法的联合应用为三阴乳腺癌的治疗带来了新希望。人类ABO血型抗原抗体系统也是人体内一种天然固有的内源性免疫系统，我们提出设想能否将肿瘤的自杀基因疗法与其相结合，利用天然免疫系统的级联反应来达到治疗肿瘤的目的。本课题组首先通过构建高表达A抗原的三阴乳腺癌细胞系，证实了B型血浆（含抗A抗体）可以通过介导CDC及ADCC效应对血型抗原A高表达的三阴乳腺癌细胞系MDA-MB-231发挥抗肿瘤作用，初步证实其可行性。本项目拟在前期工作基础上，通过转基因技术构建靶向三阴乳腺癌细胞的肿瘤特异性启动子，并结合细胞及动物实验，验证ABO天然抗原抗体系统在三阴乳腺癌基因免疫治疗中的抗肿瘤作用，为其在临床应用提供理论依据。