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

Creators: Sun, Yi; Chen, Wei; Torphy, Robert J.; Yao, Sheng; Zhu, Gefeng; Lin, Ronggui; Lugano, Roberta; Miller, Emily N.; Fujiwara, Yuki; Bian, Li; Zheng, Linghua; Anand, Sudarshan; Gao, Fan; Zhang, Weizhou; Ferrara, Sarah E.; Goodspeed, Andrew E.; Dimberg, Anna; Wang, Xiao-Jing; Edil, Barish H.; Barnett, Carlton C.; Schulick, Richard D.; Chen, Lieping; Zhu, Yuwen

Abstract

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.

Additional Information

© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an article distributed under the terms of the Science Journals Default License. Submitted 19 May 2020; Resubmitted 23 March 2021; Accepted 20 May 2021; Published 28 July 2021. We thank B. Cadugan for manuscript editing, the Human Immunology & Immunotherapy Initiative (HI3) and the Advanced Light Microscopy Core Facility at the University of Colorado Anschutz Medical Campus (AMC) for flow cytometry and immunofluorescence analyses, the Tissue Biobanking and Histology Shared Resource at UCCC for obtaining cancer specimens, the Functional Genomics Shared Resource at UCCC for shRNA constructs, the Genomics and Microarray Shared Resource at UCCC for RNA-seq, the Biophysics Core at the University of Colorado AMC for microscale thermophoresis (MST) analysis, L. Zheng at Johns Hopkins University for the KPC cell line, and R. Kedl for animal irradiation. This study is partially supported by NIH P30CA046934 (to R.D.S.); the Wings of Hope for Pancreatic Research (to Y.Z.); the Research Scholar Grant, RSG-17-106-01 LIB, from the American Cancer Society (to Y.Z.); NIH R01HL143803 (to S.A.); NIH R01-DE028420 (to X.J.W.); VA Merit Award I01 BX003232 (to X.J.W.); NIH CA196530 (to L.C.); and an endowment from United Technologies Corporation (to L.C.). Author contributions: Y.S., L.C., and Y.Z. conceived the project, designed experiments, and wrote the manuscript. Y.S., W.C., R.J.T., S.Y., G.Z., R. Lin, R. Lugano, E.N.M., Y.F., L.B., and L.Z. performed experiments and collected data. Y.S., F.G., S.E.F., and A.E.G. analyzed bioinformatics data. S.A., W.Z., A.D., X.-J.W., B.H.E., C.C.B., and R.D.S. provided resources and critical comments of the manuscript. R.D.S., L.C., and Y.Z. supervised the project. Competing interests: Y.Z. and R.D.S. receive sponsored research grant support from GlaxoSmithKline. Y.Z. consults for Dynamicure Biotechnology. R.D.S consults for NOILE Immune. L.C. serves on the scientific advisory board/board of directors of NextCure, Zai Lab, Pfizer, Vcanbio, Junshi, GenomiCare, and Tayu and has sponsored research funds from NextCure, Tayu, and Boehringer Ingelheim. S.Y. is employed by TopAlliance Biosciences Inc. and Shanghai Junshi Biosciences Inc. L.C., R.D.S, Y.S., and Y.Z. filed a patent (PCT/US2020/052681) titled, "Methods and compositions for treating a disease or disorder," containing some of the findings in the manuscript. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. mAbs for mCD93 (7C10) and mIGFBP7 (2C6) are available from University of Colorado Anschutz Medical Campus upon completion of a material transfer agreement. The RNA-seq data of tumor-associated ECs in Fig. 1F have been deposited in the GEO under accession no. GSE173658.

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Supplemental Material - abc8922_Data_file_S1.xlsx

Supplemental Material - abc8922_SM.pdf

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