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

Research output: Contribution to journalArticlepeer-review

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-b1, 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.

Original languageEnglish (US)
Article numbere52253
Pages (from-to)1-21
Number of pages21
JournaleLife
Volume9
DOIs
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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