Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Epublish 119 citations
PubMed: 32909947 DOI: 10.7554/eLife.52253
Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.
Elife 9
Authors: Xin Cui, Chao Ma, Varshini Vasudevaraja, Jonathan Serrano, Jie Tong, Yansong Peng, Michael Delorenzo, Guomiao Shen, Joshua Frenster, Renee-Tyler Tan Morales, Weiyi Qian, Aristotelis Tsirigos, Andrew S Chi, Rajan Jain, Sylvia C Kurz, Erik P Sulman, Dimitris G Placantonakis, Matija Snuderl, Weiqiang Chen
Affiliations
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States. Department of Biomedical Engineering, New York University, Brooklyn, United States. Department of Biomedical Engineering, Jinan University, Guangzhou, China.
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States. Department of Biomedical Engineering, New York University, Brooklyn, United States.
- Department of Pathology, NYU Langone Health, New York, United States.
- Department of Biomedical Engineering, New York University, Brooklyn, United States.
- Stem Cell Biology Program, NYU School of Medicine, New York, United States.
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States.
- Perlmutter Cancer Center, NYU Langone Health, New York, United States.
- Department of Neurology, NYU Langone Health, New York, United States.
- Department of Neuroradiology, NYU Langone Health, New York, United States.
- Department of Neurosurgery, NYU Langone Health, New York, United States.
- Department of Radiation Oncology, NYU Langone Health, New York, United States.
- Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States. Department of Biomedical Engineering, New York University, Brooklyn, United States. Perlmutter Cancer Center, NYU Langone Health, New York, United States.
Abstract
Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
MeSH
Biological Science Disciplines, Glioblastoma, Immunotherapy, Cells, Neoplasms, T-Lymphocytes, Microfluidics, Tumor Microenvironment, Tumor-Associated Macrophages
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