STAT1-TINCR-miR-199a-5p-PD-L1信号轴促进三阴性乳腺癌免疫逃逸的机制研究

乳腺癌是最常见的女性恶性肿瘤，其中三阴性乳腺癌具有高度异质性故复发转移风险最高，该异质性也导致了细胞免疫逃逸从而对免疫治疗不敏感。PD-L1抑制剂响应率低是三阴性乳腺癌一线化疗失败的主要原因，但是分子机制并不完全清楚。长链非编码RNA（LncRNA）参与肿瘤发生发展等多个过程，但其在乳腺癌细胞免疫逃逸方面的研究仍然凤毛麟角。申请人对乳腺癌新辅助样本行转录组测序，识别lncRNA TINCR在PD-L1抑制剂不敏感的病人中显著上调。本课题组前期研究发现TINCR与三阴性乳腺癌免疫逃逸相关。本课题拟利用病人组织样本、细胞学、动物学、分子生物学、生物信息学、免疫学等多种研究方法揭示TINCR通过ceRNA方式和表观遗传方式介导TNBC免疫逃逸，为临床攻克三阴性乳腺癌免疫逃逸提供理论依据和药物作用靶点。

Breast cancer is the most common female malignant tumor. Triple-negative breast cancer is highly heterogeneous and therefore has the highest risk of recurrence and metastasis. This heterogeneity also leads to immune escape and insensitivity to immunotherapy. The low response rate of PD-L1 inhibitors is the main reason for the failure of first-line chemotherapy for triple-negative breast cancer, but the molecular mechanism is not completely clear. Long non-coding RNA (LncRNA) is involved in many processes such as tumorigenesis and development, but its research on breast cancer cell immune escape is still rare. The applicant performed transcriptome sequencing on neoadjuvant samples of breast cancer and identified that lncRNA TINCR was significantly up-regulated in patients who were insensitive to PD-L1 inhibitors. The previous research of our group found that TINCR is related to the immune escape of triple-negative breast cancer. This project intends to use patient tissue samples, cytology, zoology, molecular biology, bioinformatics, immunology and other research methods to reveal that TINCR mediates TNBC immune escape through ceRNA and epigenetic methods, providing theoretical basis and drug targets for clinically attacking immune escape of triple-negative breast cancer.