基于Collagen/GPVI通路调控肿瘤基质屏障/凝血屏障增强anti-PD-1治疗乳腺癌药效及机制研究

乳腺癌组织内肿瘤相关成纤维细胞（Cancer associated fibroblasts, CAFs）经Collagen/GPVI通路与血小板细胞形成的基质屏障/凝血屏障，严重阻碍anti-PD-1治疗后CD8+CD103+T细胞瘤内浸润。申请人前期研究证实，替米沙坦（Telmisartan, Tel）通过逆转CAFs表型可抑制Collagen分泌，但其对anti-PD-1药效的影响及机制尚未明确。本项目拟构建响应肿瘤氧化还原环境的聚合物前药（Hp-ss-Tel）。通过乳腺癌模型研究Hp-ss-Tel增强anti-PD-1治疗乳腺癌的药效；阐明Hp-ss-Tel调控肿瘤基质屏障/凝血屏障促进CD8+CD103+T细胞浸润的机制；运用分子生物学手段，研究Hp-ss-Tel通过Collagen/GPVI通路调控肿瘤基质屏障/凝血屏障分子机制，为联合anti-PD-1的免疫疗法设计提供新思路。

The stroma barrier/coagulation barrier formed by cancer associated fibroblasts (CAFs) with platelet cells via Collagen/GPVI pathway in breast cancer tissues severely hinders CD8+CD103+T cell infiltration after anti-PD-1 treatment. Our previous studies have confirmed that Telmisartan (Tel) inhibits the secretion of collagen fibers by reversing the phenotype of CAFs. Besides, CAFs can interact with platelet cells via Collagen/GPVI pathway to form stroma barrier and coagulation barrier, however, its effect on anti-PD-1 efficacy and its mechanism are not yet clear. This project plans to use dithiol to connect Tel and heparin sodium to prepare a prodrug (Hp-ss-Tel) that responds to the tumor redox environment. To confirm that Hp-ss-Tel can enhance the efficacy of anti-PD-1 in the treatment of breast cancer in vivo; To clarify the mechanism of Hp-ss-Tel to promote the infiltration of CD8+CD103+ T cells by regulating the tumor stroma barrier/coagulation barrier by molecular biology; To study the relevant mechanism that Hp-ss-Tel regulates the tumor stroma barrier/coagulation barrier through Collagen/GPVI pathway, which provides new ideas for the strategy of combined therapies with anti-PD-1.