Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis

  • Biomaterials. 2018 Apr;161:164-178. doi: 10.1016/j.biomaterials.2018.01.053.
Xin Cui  1 ,  Renee-Tyler Tan Morales  1 ,  Weiyi Qian  1 ,  Haoyu Wang  1 ,  Jean-Pierre Gagner  2 ,  Igor Dolgalev  2 ,  Dimitris Placantonakis  3 ,  David Zagzag  4 ,  Luisa Cimmino  2 ,  Matija Snuderl  2 ,  Raymond H W Lam  5 ,  Weiqiang Chen  6
Affiliations
  • 1. Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA.
  • 2. Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
  • 3. Department of Neurosurgery, New York University School of Medicine, New York, NY 10016, USA.
  • 4. Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Neurosurgery, New York University School of Medicine, New York, NY 10016, USA.
  • 5. Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong. Electronic address: [email protected].
  • 6. Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, NY 11201, USA. Electronic address: [email protected].
PMID: 29421553 DOI: 10.1016/j.biomaterials.2018.01.053
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.

Keywords
Angiogenesis; ECM; Endothelial-macrophage interaction; Glioblastoma.
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