癌症研究
自噬
肿瘤微环境
生物
癌症
封锁
血管生成
免疫学
受体
细胞凋亡
肿瘤细胞
遗传学
生物化学
作者
Agnieszka Chryplewicz,Julie Scotton,Mélanie Tichet,Anoek Zomer,Ksenya Shchors,Johanna A. Joyce,Krisztián Homicskó,Douglas Hanahan
出处
期刊:Cancer Cell
[Elsevier]
日期:2022-10-01
卷期号:40 (10): 1111-1127.e9
被引量:45
标识
DOI:10.1016/j.ccell.2022.08.014
摘要
Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.
科研通智能强力驱动
Strongly Powered by AbleSci AI