Breg细胞调控her-2阳性乳腺癌吡咯替尼耐药的机制研究

HER2过表达型乳腺癌是侵袭性强，预后差的一种乳腺癌亚型，占乳腺癌的20-30%。络氨酸激酶抑制剂（TKI）是乳腺癌一线抗HER2治疗失败后的优选，其中吡咯替尼是首个中国自主研发的不可逆TKI药物（anti-HER1/2/4），尽管疗效显著，但仍有肿瘤耐药的问题。我们通过单细胞测序对比吡咯替尼耐药与非耐药人乳腺癌组织，发现耐药病灶中B细胞显著增加，且具有CD24+CD27+免疫抑制B细胞的表型；体外研究也提示吡咯替尼耐药乳腺癌细胞能够诱导CD24+CD27+Breg极化，具有免疫抑制功能。基于此本项目拟通过单细胞测序等多组学解析吡咯替尼耐药乳腺癌的免疫微环境特征；同时通过体内外实验明确吡咯替尼耐药乳腺癌极化CD24+CD27+Breg的免疫学机制，及靶向B细胞对改善吡咯替尼耐药的价值。本项目从B细胞的角度阐述免疫微环境对乳腺癌吡咯替尼耐药的调控作用，为开发相应治疗策略提供理论与实验依据。

HER-2 positive breast cancer has the highest malignancy and the worst prognosis. TKI is the best choice when the first-line therapy has failed for advanced HER-2 positive breast cancer. Of all TKIs, pyrotinid is the first anti-HER1/2/4 drug that is developed by Chinese own. Though it is useful in advanced breast cancer, resistance occurs not rare. We compared the tumor tissues before and after developing pyrotinib resistance with single-cell sequencing technique. Result shows that the B cells are greater in breast cancer tissue that has developed pyrotinib resistance than that has not, and the B cells are all CD24+CD27+. In vitro experiment also shows that pyrotinib resistant breast cancer can induce the polarization of CD24+CD27+Breg cells and then these Breg cells got the immunosuppression ability. We want to describe the micro immune environment in pyrotinib resistant breast cancer and the immune mechanisms that how the CD24+CD27+Breg cells got polarized, and whether it can reverse the pyrotinib resistance for breast cancer by targeting at Breg cells.