Doxorubicin-polyglycerol-nanodiamond composites stimulate glioblastoma cell immunogenicity through activation of autophagy. (1st March 2019)

• Record Type: Journal Article
• Authors: Li, Tong-Fei; Xu, Yong-Hong; Li, Ke; Wang, Chao; Liu, Xin; Yue, Yuan; Chen, Zhuo; Yuan, Shen-Jun; Wen, Yu; Zhang, Quan; Han, Min; Komatsu, Naoki; Zhao, Li; Chen, Xiao
• Is Part Of: Acta biomaterialia. Volume 86(2019)
• Page Start: 381
• Page End: 394
• Publication Date: 2019-03-01
• Subjects: ATP adenosine triphosphate -- BBB blood-brain barrier -- BCA bicinchoninic acid -- Baf Bafilomycin -- C11-fluor 5-(N-dodecanoyl)aminofluorescein -- DC dendritic cells -- ICD immunogenic cell death -- IHC immunohistochemistry -- mDC mouse dendritic cells -- mLC mouse lymphocytes -- CFSE 5(6)-carboxyfluorescein diacetate succinimidyl ester -- GFP green fluorescent protein -- GCM GC-conditioned culture medium -- CRT calreticulin -- DAMPs damage-associated molecular patterns -- DOX doxorubicin -- HMGB1 high mobility group protein B1 -- HSP90 heat shock protein 90 -- FACS flow cytometry -- GBM glioblastoma -- GC glioblastoma cells -- MHC-I major histocompatibility complex I molecules -- MHC-II major histocompatibility complex II molecules -- ND-GCM Nano-DOX-treated GCM -- ND-GCM-P precipitates yielded from 104 g-centrifugation of ND-GCM -- ND-GCM-S supernatants yielded from 104 g-centrifugation of ND-GCM -- IL interleukin -- nanodiamond-polyglycerol-doxorubicin Nano-DOX -- ND nanodiamonds -- Nano-DOX-mDC Nano-DOX-loaded mDC -- PBS phosphate buffered saline -- PEI polyethylenimine -- PG polyglycerol -- PVDF polyvinylidene fluoride -- TBST Tris Buffered Saline with Tween® 20 -- SD standard deviation -- SQSTM1/p62 sequestosome 1 -- Repa rapamycin -- 3-MA 3-methyladenine -- Wort wortmannin; Nanodiamond -- Doxorubicin -- Glioblastoma -- Immunogenicity -- Autophagy; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2019.01.020
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: Abstract: Immunosuppression is a salient feature of GBM associated with the disease's grim prognosis and the limited success of anti-GBM immunotherapy. Stimulating immunogenicity of the GBM cells (GC) is a promising approach to subverting the GBM-associated immunosuppression. We had previously devised a drug composite based on polyglycerol-functionalized nanodiamonds bearing doxorubicin (Nano-DOX) and demonstrated that Nano-DOX effectively modulated GBM's immunosuppressive microenvironment through stimulating the immunogenicity of GC and initiated anti-GBM immune responses. The present study now explored the mechanism of Nano-DOX's immunostimulatory action. Nano-DOX was found to induce autophagy rather than apoptosis in GC and stimulated GC to emit antigens and damage-associated molecular patterns (DAMPs) that are potent adjuvants, which resulted in enhanced activation of dendritic cells (DC). Heightened autophagosome release was observed in Nano-DOX-treated GC but was shown not to be a major channel of antigen donation. Blocking autophagy in GC not only reduced Nano-DOX-stimulated GC antigen donation and DAMPs emission, but also efficiently attenuated DC activation stimulated by Nano-DOX-treated GC. Taken together, these findings suggest that activation of autophagy is a central mechanism whereby Nano-DOX stimulates GC's immunogenicity. Our work provides new insight on how nanotechnology can be applied to therapeutically modulate the GBM immune microenvironment by harnessing autophagy in the cancer cells. Statement of Significance: Immunosuppression is a salient feature of GBM associated with the grim prognosis of the disease and the limited success of anti-GBM immunotherapy. We demonstrated that Doxorubicin-polyglycerol-nanodiamond composites could activate autophagy in GBM cells and thereby stimulate the immunogenecity of GBM cells. This discovery 1, sheds new light on how nanotechnology could be applied to therapeutically modulate the tumor immune microenvironment, and 2, provides a powerful tool for subverting the GBM's immunosuppressive microenvironment, which has great therapeutic potential for the treatment of GBM.