Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
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
Xin Cui
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
Varshini Vasudevaraja
Department of Pathology, NYU Langone Health, New York, United States
Jonathan Serrano
Department of Pathology, NYU Langone Health, New York, United States
Jie Tong
Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States; Department of Biomedical Engineering, New York University, Brooklyn, United States
Yansong Peng
Department of Biomedical Engineering, New York University, Brooklyn, United States
Michael Delorenzo
Department of Pathology, NYU Langone Health, New York, United States
Guomiao Shen
Department of Pathology, NYU Langone Health, New York, United States
Joshua Frenster
Stem Cell Biology Program, NYU School of Medicine, New York, United States
Renee-Tyler Tan Morales
Department of Biomedical Engineering, New York University, Brooklyn, United States
Weiyi Qian
Department of Mechanical and Aerospace Engineering, New York University, Brooklyn, United States
Aristotelis Tsirigos
Department of Pathology, NYU Langone Health, New York, United States
Andrew S Chi
Perlmutter Cancer Center, NYU Langone Health, New York, United States; Department of Neurology, NYU Langone Health, New York, United States
Rajan Jain
Department of Neuroradiology, NYU Langone Health, New York, United States; Department of Neurosurgery, NYU Langone Health, New York, United States
Sylvia C Kurz
Perlmutter Cancer Center, NYU Langone Health, New York, United States; Department of Neurosurgery, NYU Langone Health, New York, United States
Erik P Sulman
Perlmutter Cancer Center, NYU Langone Health, New York, United States; Department of Radiation Oncology, NYU Langone Health, New York, United States
Dimitris G Placantonakis
Perlmutter Cancer Center, NYU Langone Health, New York, United States; Department of Neurosurgery, 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
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.