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Synergistic checkpoint-blockade and radiotherapy–radiodynamic therapy via an immunomodulatory nanoscale metal–organic framework

Nature Biomedical Engineering volume 6, pages 144–156 (2022)Cite this article

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Abstract

Checkpoint blockade elicits durable responses in immunogenic cancers, but it is largely ineffective in immunologically ‘cold’ tumours. Here we report the design, synthesis and performance of a bismuth-based nanoscale metal–organic framework that modulates the immunological and mechanical properties of the tumour microenvironment for enhanced radiotherapy–radiodynamic therapy. In mice with non-immunogenic prostate and pancreatic tumours irradiated with low X-ray doses, the intratumoural injection of the radiosensitizer mediated potent outcomes via the repolarization of immunosuppressive M2 macrophages into immunostimulatory M1 macrophages, the reduction of the concentration of intratumoural transforming growth factor beta (TGF-β) and of collagen density, and the inactivation of cancer-associated fibroblasts. When intravenously injected in combination with checkpoint-blockade therapy, the radiosensitizer mediated the reversal of immunosuppression in primary and distant tumours via the systemic reduction of TGF-β levels, which led to the downregulation of collagen expression, the stimulation of T-cell infiltration in the tumours and a robust abscopal effect. Nanoscale radiosensitizers that stimulate anti-tumour immunity and T-cell infiltration may enhance the therapeutic outcomes of checkpoint blockade in other tumour types.

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Fig. 1: Characterization and radiosensitization of Bi-DBP.
Fig. 2: Bi-DBP-mediated radiosensitization and immunogenic cell death.
Fig. 3: In vivo radiosensitization and biomechanical modulation mediated by Bi-DBP.
Fig. 4: Abscopal effect and anti-tumour immunity mediated by Bi-DBP.
Fig. 5: Reversal of systemic immunosuppression via modulated biomechanics.
Fig. 6: Scheme of Bi-DBP-mediated RT–RDT modulated biomechanics to promote T-cell infiltration.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for Figs. 3 and 4 are provided with this paper. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

We thank Y. Song for experimental help; the late O. Schneewind of the Department of Microbiology at the University of Chicago for help with the macrophage repolarization studies; and the National Cancer Institute (U01–CA198989 and 1R01CA253655), the Department of Defense (PC170934P2), the University of Chicago Medicine Comprehensive Cancer Center (NIH CCSG: P30 CA014599) and the Ludwig Institute for Metastasis Research for funding support.

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  1. These authors contributed equally: Kaiyuan Ni, Ziwan Xu.

Authors and Affiliations

  1. Department of Chemistry, The University of Chicago, Chicago, IL, USA

    Kaiyuan Ni, Ziwan Xu, August Culbert, Taokun Luo, Nining Guo, Tong Wu & Wenbin Lin

  2. Department of Radiation and Cellular Oncology and The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA

    Nining Guo, Kaiting Yang, Ralph R. Weichselbaum, Michael T. Spiotto & Wenbin Lin

  3. Department of Radiology, The University of Chicago, Chicago, IL, USA

    Erik Pearson, Ben Preusser & Patrick La Riviere

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  1. Kaiyuan Ni
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Contributions

K.N. and W.L. conceived the project. K.N., Z.X., A.C. and T.L. performed the experiments and analysed the results. E.P., B.P. and P.L.R. performed the radioluminescence test, and N.G. and T.W. assisted with the qPCR analysis. M.T.S. and N.G. generated the spontaneous TRAMP model. N.G. and K.Y. performed intraprostatic injection. K.N., Z.X., A.C., R.R.W., M.T.S. and W.L. wrote the manuscript.

Corresponding author

Correspondence to Wenbin Lin.

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Competing interests

W.L. is founder of Coordination Pharmaceuticals, which licensed the nMOF technology from the University of Chicago. R.R.W. is a consultant to Coordination Pharmaceuticals. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Structure of Bi10O8 SBUs.

Views of Bi10O8 SBUs in Bi-BPDC along the crystallographic a-axis or b-axis (a) and c-axis (b). Purple: bismuth; red: oxygen; blue: nitrogen; grey: carbon.

Extended Data Fig. 2 Crystal structure of Bi-DBP.

Modelled crystal structures of Bi-DBP projected along the a-axis (a), the b-axis (b), and the c-axis (c) and Bi10O8 SBU (d). Purple: bismuth; red: oxygen; blue: nitrogen; grey: carbon.

Extended Data Fig. 3 Immune profiling on bilateral TRAMP-C2 model.

Percentages of tumour-infiltrating leucocytes with respect to the total live cells from TRAMP-C2 tumour-bearing mice treated with PBS (–), PBS (+), aPD-L1 (+), Bi-DBP (+), Bi-DBP (–) + αPD-L1, or Bi-DBP (+) + αPD-L1. Data are expressed as means ± s.d., n = 5 for biological replicates. P-value by two-sided student t-test. Central lines, bounds of box and whiskers represent mean values, 25% to 75% of the range of data and 1.5-fold of interquartile range away from outliers, respectively. The result was obtained without repetition.

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Supplementary methods, figures and tables.

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Source data

Source data for Fig. 3

Tumour-growth data in Fig. 3a,b.

Source data for Fig. 4

Tumour-growth data in Fig. 4a,b,d,e.

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Ni, K., Xu, Z., Culbert, A. et al. Synergistic checkpoint-blockade and radiotherapy–radiodynamic therapy via an immunomodulatory nanoscale metal–organic framework. Nat Biomed Eng 6, 144–156 (2022). https://doi.org/10.1038/s41551-022-00846-w

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