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Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection

Nature Nanotechnology volume 16, pages 538–548 (2021)Cite this article

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Abstract

Immunotherapies have revolutionized intervention strategies for many primary cancers, but have not improved the outcomes of glioblastoma multiforme (GBM), which remains one of the most lethal malignant cerebral tumours. Here we present an injectable hydrogel system that stimulates tumoricidal immunity after GBM surgical resection, which mitigates its relapse. The hydrogel comprises a tumour-homing immune nanoregulator, which induces immunogenic cell death and suppression of indoleamine 2,3-dioxygenase-1, and chemotactic CXC chemokine ligand 10, for a sustained T-cell infiltration. When delivered in the resected tumour cavity, the hydrogel system mimics a ‘hot’ tumour-immunity niche for attacking residual tumour cells and significantly suppresses postoperative GBM recurrence. Our work provides an alternative strategy for conferring effective tumoricidal immunity in GBM patients, which may have a broad impact in the immunotherapy of ‘cold’ tumours after surgical intervention.

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Fig. 1: Bioinformatic analysis of immunosuppression-related biomarkers and the survival of patients with GBM and a schematic illustration of the intracavity-injected hydrogel system imitating a tumour immunity niche for regressing postresection tumour relapse.
Fig. 2: Design and characterization of the injectable hydrogel system as a drug-delivery depot.
Fig. 3: Cellular uptake of THINR and the efficiency of ICD and suppression of IDO1 in tumour cells triggered by THINR.
Fig. 4: Antitumour efficacy of each formulation in an orthotopic intracranial GBM model.
Fig. 5: Intracavity-injected hydrogel system significantly suppressed tumour recurrence and prolonged the survival of postresection GBM mice.
Fig. 6: The immune modulation potencies of the intracavity-injected hydrogel system in imitating a hot tumour immunity in brain tissue.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request. IDH1 mRNA and IDO1 mRNA expression in GBM patients and healthy people isolated from TCGA and Genotype-Tissue Expression determined by Gene Expression Profiling Interactive Analysis (http://gepia.cancer-pku.cn/detail.php?gene=&clicktag=boxplot). Survival analysis of GBM patients with high and low IDH1 expression was isolated from GEPIA (http://gepia.cancer-pku.cn/detail.php?gene=&clicktag=survival). Survival analysis of GBM patients with high and low IDO1 expression was download from OncoLnc (http://www.oncolnc.org/kaplan/?cancer=GBM&gene_id=3620&raw=IDO1&species=mRNA).

Code availability

The codes used to analyse the data in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by Shandong Provincial Key Research and Development Program (Major Scientific and Technological Innovation Project) (2019JZZY021013), Shandong Provincial Key Research and Development Program (2019GSF108080), Funds for Youth Interdisciplinary and Innovation Research Groups of Shandong University (2020QNQT003), National Natural Science Foundation of China (81874419) and Major New Drug Creation Project of China (2017ZX09301064). We thank Y. Yu, X.-M. Yu, J. Zhang, M.-L. Wu and L.-M. Wang for technical supporting at the Advanced Medical Research Institute/Translational Medicine Core Facility of the Advanced Medical Research Institute, Shandong University. We thank G.-R. Zhang for the MRI technical support at the Department of Radiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University.

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  1. These authors contributed equally: Jing Zhang, Chen Chen.

Authors and Affiliations

  1. Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P. R. China

    Jing Zhang, Chen Chen, Shengchang Zhang, Wei Du, Rui Zhang, Ying Liu & Xinyi Jiang

  2. Department of Radiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P. R. China

    Anning Li

  3. Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, P. R. China

    Weiqiang Jing

  4. Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, P. R. China

    Peng Sun & Jibiao Wu

  5. Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, P. R. China

    Xueyang Huang & Aihua Gong

  6. Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, P. R. China

    Yingchao Liu

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Contributions

J.Z., C.C. and X.J. conceived the project and designed the experiments. J.Z., C.C., Yingchao Liu. and R.Z. contributed to the immunohistochemical staining. J.Z. and C.C. performed the fabrication and characterization of the hydrogel system. X.H. and A.G. contributed to the cell culture. J.Z., C.C., A.L., P.S., R.Z. and X.J. contributed to the in vivo tumourigenesis and antitumour activity experiments. W.J. and X.J. contributed to the western blotting. J.Z., C.C., S.Z., W.D., Ying Liu and R.Z. contributed to the ELISA, H&E staining and flow cytometry assays. A.L., P.S. and Ying Liu performed live animal imaging and analysis. J.Z., C.C. and X.J. analysed and interpreted the data in this study. J.Z., C.C. and X.J. wrote the manuscript draft. The final draft of the manuscript was approved by all the co-authors.

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Correspondence to Xinyi Jiang.

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The authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Derek Wainwright and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhang, J., Chen, C., Li, A. et al. Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection. Nat. Nanotechnol. 16, 538–548 (2021). https://doi.org/10.1038/s41565-020-00843-7

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