Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt de bloquer la voie de signalisation de l'antigène CD93 pour normaliser les vaisseaux de la tumeur, faciliter ainsi l'accès des agents anticancéreux aux cellules cancéreuses et améliorer l'efficacité des immunothérapies
Solid tumors have structurally abnormal blood vessels that lead to decreased drug accessibility and effector T cell infiltration into the tumor. Targeting this abnormal vasculature could potentially improve response to therapy. Here, Sun and colleagues identified the interaction between CD93 and insulin-like growth factor binding protein 7 as important for the formation of abnormal tumor vasculature. Treatment with monoclonal antibodies to inhibit this interaction led to improved tumor perfusion in mice, resulting in increased drug delivery and an increase in effector T cells within the tumor, sensitizing the tumors to immune checkpoint inhibition. Further study is required to assess whether targeting the CD93 pathway improves treatment response in humans.The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti–programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.