TY - JOUR
T1 - Dissecting the immunosuppressive tumor microenvironments in glioblastoma-on-a-chip for optimized Pd-1 immunotherapy
AU - Cui, Xin
AU - Ma, Chao
AU - Vasudevaraja, Varshini
AU - Serrano, Jonathan
AU - Tong, Jie
AU - Peng, Yansong
AU - Delorenzo, Michael
AU - Shen, Guomiao
AU - Frenster, Joshua
AU - Morales, Renee Tyler Tan
AU - Qian, Weiyi
AU - Tsirigos, Aristotelis
AU - Chi, Andrew S.
AU - Jain, Rajan
AU - Kurz, Sylvia C.
AU - Sulman, Erik P.
AU - Placantonakis, Dimitris G.
AU - Snuderl, Matija
AU - Chen, Weiqiang
N1 - Funding Information:
This work was supported in part by the US National Institutes of Health (R35GM133646 to WC, R21EB025406 to WC and MS), the National Science Foundation (CBET1701322 to WC), and the Friedberg Charitable Foundation (to MS). DGP was supported by NIH/NINDS (R01NS102665), NIH/ NIBIB (R01EB028774), New York State Stem Cell Science (IIRP C32595GG), NYU Grossman School of Medicine, and German Research Foundation (FOR2149).
Publisher Copyright:
© Cui et al.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Glioblastoma/therapy
KW - Immunotherapy/instrumentation
KW - Lab-On-A-Chip Devices
KW - Programmed Cell Death 1 Receptor/metabolism
KW - Tumor Microenvironment/immunology
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U2 - 10.7554/ELIFE.52253
DO - 10.7554/ELIFE.52253
M3 - Article
C2 - 32909947
AN - SCOPUS:85090818515
SN - 2050-084X
VL - 9
SP - 1
EP - 21
JO - eLife
JF - eLife
M1 - e52253
ER -