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Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy

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 sys...

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Autores principales: Cui, Xin, Ma, Chao, Vasudevaraja, Varshini, Serrano, Jonathan, Tong, Jie, Peng, Yansong, Delorenzo, Michael, Shen, Guomiao, Frenster, Joshua, Morales, Renee-Tyler Tan, Qian, Weiyi, Tsirigos, Aristotelis, Chi, Andrew S, Jain, Rajan, Kurz, Sylvia C, Sulman, Erik P, Placantonakis, Dimitris G, Snuderl, Matija, Chen, Weiqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556869/
https://www.ncbi.nlm.nih.gov/pubmed/32909947
http://dx.doi.org/10.7554/eLife.52253
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author Cui, Xin
Ma, Chao
Vasudevaraja, Varshini
Serrano, Jonathan
Tong, Jie
Peng, Yansong
Delorenzo, Michael
Shen, Guomiao
Frenster, Joshua
Morales, Renee-Tyler Tan
Qian, Weiyi
Tsirigos, Aristotelis
Chi, Andrew S
Jain, Rajan
Kurz, Sylvia C
Sulman, Erik P
Placantonakis, Dimitris G
Snuderl, Matija
Chen, Weiqiang
author_facet Cui, Xin
Ma, Chao
Vasudevaraja, Varshini
Serrano, Jonathan
Tong, Jie
Peng, Yansong
Delorenzo, Michael
Shen, Guomiao
Frenster, Joshua
Morales, Renee-Tyler Tan
Qian, Weiyi
Tsirigos, Aristotelis
Chi, Andrew S
Jain, Rajan
Kurz, Sylvia C
Sulman, Erik P
Placantonakis, Dimitris G
Snuderl, Matija
Chen, Weiqiang
author_sort Cui, Xin
collection PubMed
description 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.
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spelling pubmed-75568692020-10-16 Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy Cui, Xin Ma, Chao Vasudevaraja, Varshini Serrano, Jonathan Tong, Jie Peng, Yansong Delorenzo, Michael Shen, Guomiao Frenster, Joshua Morales, Renee-Tyler Tan Qian, Weiyi Tsirigos, Aristotelis Chi, Andrew S Jain, Rajan Kurz, Sylvia C Sulman, Erik P Placantonakis, Dimitris G Snuderl, Matija Chen, Weiqiang eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2020-09-10 /pmc/articles/PMC7556869/ /pubmed/32909947 http://dx.doi.org/10.7554/eLife.52253 Text en © 2020, Cui et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Cui, Xin
Ma, Chao
Vasudevaraja, Varshini
Serrano, Jonathan
Tong, Jie
Peng, Yansong
Delorenzo, Michael
Shen, Guomiao
Frenster, Joshua
Morales, Renee-Tyler Tan
Qian, Weiyi
Tsirigos, Aristotelis
Chi, Andrew S
Jain, Rajan
Kurz, Sylvia C
Sulman, Erik P
Placantonakis, Dimitris G
Snuderl, Matija
Chen, Weiqiang
Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title_full Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title_fullStr Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title_full_unstemmed Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title_short Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy
title_sort dissecting the immunosuppressive tumor microenvironments in glioblastoma-on-a-chip for optimized pd-1 immunotherapy
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556869/
https://www.ncbi.nlm.nih.gov/pubmed/32909947
http://dx.doi.org/10.7554/eLife.52253
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