Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy

• DOI: 10.1126/scitranslmed.abc8922
• Publication Date: 2021-07-28T19:11:10Z
• Authors: Yi Sun; Wei Chen; Robert J. Torphy; Sheng Yao; Gefeng Zhu; Ronggui Lin; Roberta Lugano; Emily N. Miller; Yuki Fujiwara; Li Bian; Linghua Zheng; Sudarshan Anand; Fan Gao; Weizhou Zhang; Sarah E. Ferrara; Andrew E. Goodspeed; Anna Dimberg; Xiao-Jing Wang; Barish H. Edil; Carlton C. Barnett; Richard D. Schulick; Lieping Chen; Yuwen Zhu
• Keywords: Tumor Hypoxia

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates hypoxic tumor microenvironment that actively limits immune cell infiltration. molecular basis underpinning this dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here insulin-like growth factor binding protein 7 (IGFBP7) interacts with its CD93, subsequently demonstrated interaction contributes abnormal vasculature. Both CD93 IGFBP7 were up-regulated in tumor-associated endothelial cells. interacted via domain different from multimerin-2, the known ligand for CD93. In two mouse models, blockade of CD93/IGFBP7 by monoclonal antibodies promoted maturation reduce leakage, leading reduced hypoxia increased perfusion. mice drug delivery, resulting an improved antitumor response gemcitabine or fluorouracil. Blockade pathway triggered increase intratumoral effector T cells, thereby sensitizing checkpoint therapy. Last, analysis samples patients cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed overexpression IGFBP7/CD93 was associated poor Thus, our study identified involved approach promote favorable therapeutic intervention.