Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis

Xin Cui, Renee Tyler Tan Morales, Weiyi Qian, Haoyu Wang, Jean Pierre Gagner, Igor Dolgalev, Dimitris Placantonakis, David Zagzag, Luisa Cimmino, Matija Snuderl, Raymond H.W. Lam, Weiqiang Chen

Research output: Contribution to journalArticle

Abstract

Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin “inflammation-driven angiogenesis.” We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (αvβ3) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (αvβ3)-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (αvβ3) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies.

Original languageEnglish (US)
Pages (from-to)164-178
Number of pages15
JournalBiomaterials
Volume161
DOIs
StatePublished - Apr 2018

Keywords

  • Angiogenesis
  • ECM
  • Endothelial-macrophage interaction
  • Glioblastoma

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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  • Cite this

    Cui, X., Morales, R. T. T., Qian, W., Wang, H., Gagner, J. P., Dolgalev, I., Placantonakis, D., Zagzag, D., Cimmino, L., Snuderl, M., Lam, R. H. W., & Chen, W. (2018). Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. Biomaterials, 161, 164-178. https://doi.org/10.1016/j.biomaterials.2018.01.053