Yuan Yi, Mishra Falguni, Li Bin, Peng Guangda, Chan Payton, Yang Jenny, Liu Zhiren
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
Cancers (Basel). 2024 Jul 8;16(13):2483. doi: 10.3390/cancers16132483.
Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αβ at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αβ. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD Treg and Myeloid-derived suppressor cells (MDSCs), increases CD T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the () levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment.
纤维化基质和肿瘤血管生成在调节肿瘤免疫中发挥重要作用。我们之前报道了一种经过合理设计的蛋白质（ProAgio），它能在一个新位点靶向整合素αβ。ProAgio可诱导高表达该整合素的细胞凋亡。肿瘤中活化的癌症相关成纤维细胞（CAFs）和血管生成性内皮细胞（aECs）均高表达整合素αβ。ProAgio能同时特异性地诱导肿瘤中的CAFs和aECs凋亡。我们在此提供证据表明，ProAgio对CAFs的消耗以及对肿瘤血管生成渗漏血管的消除改变了肿瘤免疫。ProAgio可减少CD4+调节性T细胞（Treg）和髓源性抑制细胞（MDSCs），增加CD4+T细胞，并提高肿瘤中M1/M2巨噬细胞比例。ProAgio对致密纤维化基质（CAFs）的消耗降低了肿瘤周围基质区域的（）水平，从而显著增加了抗程序性死亡受体1（PDL-1）抗体向靶癌细胞的递送。ProAgio对肿瘤免疫的影响为检查点抑制剂在肺癌治疗中提供了强大的协同效应。
