PDF(Pubmed)
Abstract：
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 αvβ3 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 αvβ3. 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 CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) 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.
摘要：
纤维化间质和血管生成肿瘤血管在调节肿瘤免疫中起重要作用。我们先前报道了一种合理设计的蛋白质（ProAgio），该蛋白质在新位点靶向整合素αvβ3。ProAgio诱导表达高水平整合素的细胞的凋亡。肿瘤中活化的癌症相关成纤维细胞（CAF）和血管生成内皮细胞（aEC）均表达高水平的整合素αvβ3。ProAgio同时并特异性诱导肿瘤中CAF和aECs的凋亡。我们在此提供证据，证明ProAgio耗尽CAF和消除渗漏的肿瘤血管生成血管会改变肿瘤免疫力。ProAgio减少CD4+Treg和髓系来源的抑制细胞（MDSCs），增加CD8+T细胞，并增加肿瘤中M1/M2巨噬细胞的比例。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程序性死亡配体1（PDL-1）水平，并因此强烈增加抗PDL-1抗体向靶癌细胞的递送。ProAgio对肿瘤免疫的影响提供了检查点抑制剂对肺癌治疗的强协同作用。
