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J Control Release. 2017 Dec 28;268:128-146. doi: 10.1016/j.jconrel.2017.10.024. Epub 2017 Oct 16.

Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment.

Author information

1
Department of Pharmacology, School of Basic Medicine, Wuhan University, Donghu Avenue No.185, Wuhan 430072, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
2
Center for Lab Teaching, School of Basic Medicine, Wuhan University, Donghu Avenue No.185, Wuhan 430072, China.
3
Institute of Ophthalmological Research, Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
4
Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
5
Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
6
School of Radiation Medicine and Protection (SRMP), School of Radiation and Multidisciplinary Sciences (RAD-X), Medical College, Soochow University, Suzhou 215123, China. Electronic address: lizhao@suda.edu.cn.
7
Department of Pharmacology, School of Basic Medicine, Wuhan University, Donghu Avenue No.185, Wuhan 430072, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China. Electronic address: mornsmile@yahoo.com.

Abstract

Glioblastoma (GBM) is the most frequent and malignant brain tumor with a high mortality rate. The presence of a large population of macrophages (Mφ) in the tumor microenvironment is a prominent feature of GBM and these so-called tumor-associated Mφ (TAM) closely interact with the GBM cells to promote the survival, progression and therapy resistance of the GBM. Various therapeutic strategies have been devised either targeting the GBM cells or the TAM but few have addressed the cross-talks between the two cell populations. The present study was carried out to explore the possibility of exploiting the cross-talks between the GBM cells (GC) and TAM for modulation of the GBM microenvironment through using Nano-DOX, a drug composite based on nanodiamonds bearing doxorubicin. In the in vitro work on human cell models, Nano-DOX-loaded TAM were first shown to be viable and able to infiltrate three-dimensional GC spheroids and release cargo drug therein. GC were then demonstrated to encourage Nano-DOX-loaded TAM to unload Nano-DOX back into GC which consequently emitted damage-associated molecular patterns (DAMPs) that are powerful immunostimulatory agents as well as indicators of cell damage. Nano-DOX was next proven to be a more potent inducer of GC DAMPs emission than doxorubicin. As a result, Nano-DOX-damaged GC exhibited an enhanced ability to attract both TAM and Nano-DOX-loaded TAM. Most remarkably, Nano-DOX-damaged GC reprogrammed the TAM from a pro-GBM phenotype to an anti-GBM phenotype that suppressed GC growth. Finally, the in vivo relevance of the in vitro findings was tested in animal study. Mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mouse TAM which were found releasing drug in the GBM xenografts 24h after injection. GC damage was evidenced by the induction of DAMPs emission within the xenografts and a shift of TAM phenotype was detected as well. Taken together, our results demonstrate a novel way with therapeutic potential to harness the cross-talk between GBM cells and TAM for modulation of the tumor immune microenvironment.

KEYWORDS:

Cancer cell; Cancer-associated macrophage; Cross-talk; Glioblastoma; Nano-drug

PMID:
29051064
DOI:
10.1016/j.jconrel.2017.10.024
[Indexed for MEDLINE]

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