Probing molecular targets of VEGF inhibition, Sun et al. found that binding partners CD93 and IGFBP7 were overexpressed in endothelial cells of human and mouse tumors relative to healthy tissue. Treatment with anti-CD93 mAb (or anti-IGFBP7 mAb) in mouse tumor models normalized tumor vasculature, reduced hypoxia, and improved chemotherapy penetration and efficacy. CD93 blockade alone increased T cell tumor infiltration and reduced tumor growth, dependent on CD8+ T cells, but also increased intratumoral PD-L1 expression. Co-blockade of CD93 and PD-1 further improved tumor control and T cell infiltration.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (2) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora,
Author Info: (1) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (2) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang 310012, P. R. China. (3) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. (6) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (7) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. (8) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (9) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (10) Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. (12) Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR 97239, USA. (13) Caltech Bioinformatics Resource Center at Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA. (14) Department of Pathology, University of Florida, Gainesville, FL 32610, USA. (15) University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. (16) University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (17) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden. (18) Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Veterans Affairs Medical Center, VA Eastern Colorado Health Care System, Aurora, CO 80045, USA. (19) Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. (20) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (21) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (22) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. yuwen.zhu@cuanschutz.edu lieping.chen@yale.edu. (23) Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. yuwen.zhu@cuanschutz.edu lieping.chen@yale.edu.
