Delphinidin靶向EGFR/PD-L1通路阻断三阴性乳腺癌免疫逃逸及机制研究

三阴性乳腺癌恶性程度较高，易产生免疫逃逸。前期证实，飞燕草素delphinidin靶向EGFR抗乳腺癌生长增殖及转移。新近证实，delphinidin体外能抑制肿瘤免疫逃逸关键分子PD-L1表达。最近利用生物信息学发现，Ras/MAKP和PI3K-Akt为EGFR/PD-L1通路中的重要转导分子。Delphinidin是否靶向EGFR/PD-L1通路阻断三阴性乳腺癌免疫逃逸？亟待探讨。本项目以MDA-MB-231细胞和移植瘤模型，从体内体外角度首先证实delphinidin通过调控Ras/MAPK和PI3K-Akt分子抑制三阴性乳腺癌PD-L1合成；然后证实delphinidin通过抑制细胞膜PD-L1表达途径阻断三阴性乳腺癌免疫逃逸；最后证实delphinidin还能通过降低外泌体PD-L1含量途径阻断三阴性乳腺癌免疫逃逸。研究结果有望从植物化学物质阻断免疫逃逸的角度探索抗肿瘤的新举措。

Triple negative breast cancer (PR-/HER-2/ER-) has a high degree of malignancy and is prone to immune escape. Our previous research confirmed that the phytochemical delphinidin monomer mainly acts on EGFR to resist breast cancer growth, proliferation and metastasis. It has recently been confirmed that delphinidin can inhibit the expression of PD-L1 which is a key molecule for tumor immune escape in vivo. Furthermore, using bioinformatics analysis, we found that Ras/MAKP and PI3K-Akt are important transduction molecules in the EGFR/PD-L1 pathway. Hence, whether delphinidin has the ability to target the EGFR/PD-L1 pathway to block the immune escape of triple negative breast cancer needs to be explored urgently. The triple negative breast cancer MDA-MB-231 cell model and tumor xenograft animal model are used as research objects in this project. First, it was proposed that delphinidin might inhibit the synthesis of triple negative breast cancer PD-L1 by regulating signal molecules Ras/MAPK and PI3K-Akt in vivo and in vitro. Second, delphinidin might inhibit the tumor cell membrane PD-L1 expression pathway, increases the CD8+ and CD4+ T cell immune activity, and block the immune escape of triple negative breast cancer. Finally, in vivo and in vitro, it was anticipated that delphinidin can block the pathway of PD-L1 in exosomes, thus inhibiting triple negative breast cancer immune escape. The results are expected to explore new anti-tumor initiatives from the perspective of phytochemicals blocking immune escape.