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

• DOI: 10.7554/elife.52253
• Publication Date: 2020-09-10T15:01:47Z
• Authors: Xin Cui; Chao Ma; Varshini Vasudeva...; Jonathan Serrano; Jie Tong; Yansong Peng; Michael Delorenzo; Guomiao Shen; Joshua Frenster; Renee-Tyler Tan M...; Weiyi Qian; Aristotelis Tsirigos; Andrew S Chi; Rajan Jain; Sylvia C Kurz; Erik P Sulman; Dimitris G Placan...; Matija Snuderl; Weiqiang Chen
• Keywords: Temozolomide; Immune checkpoint; Cancer 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 system dissect of microenvironments optimize anti-PD-1 for different GBM subtypes. Our clinical experimental analyses demonstrated that molecularly distinct subtypes have epigenetic immune signatures may lead mechanisms. The real-time analysis GBM-on-a-Chip showed mesenchymal niche attracted low number allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), expressed elevated PD-1/PD-L1 checkpoints TGF-β1, IL-10, CSF-1 cytokines compared proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, co-administered CSF-1R BLZ945 ablate M2-TAMs strengthened T-cell functionality apoptosis on-chip. ex vivo provides an avenue personalized screening immunotherapies patients.