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Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds

Nature Biomedical Engineering volume 7, pages 56–71 (2023)Cite this article

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Abstract

A tumour microenvironment abundant in regulatory T (Treg) cells aids solid tumours to evade clearance by effector T cells. Systemic strategies to suppress Treg cells or to augment immunity can elicit autoimmune side effects, cytokine storms and other toxicities. Here we report the design, fabrication and therapeutic performance of a biodegradable macroporous scaffold, implanted peritumourally, that releases a small-molecule inhibitor of transforming growth factor β to suppress Treg cells, chemokines to attract effector T cells and antibodies to stimulate them. In two mouse models of aggressive tumours, the implant boosted the recruitment and activation of effector T cells into the tumour and depleted it of Treg cells, which resulted in an ‘immunological abscopal effect’ on distant metastases and in the establishment of long-term memory that impeded tumour recurrence. We also show that the scaffold can be used to deliver tumour-antigen-specific T cells into the tumour. Peritumourally implanted immunomodulatory scaffolds may represent a general strategy to enhance T-cell immunity and avoid the toxicities of systemic therapies.

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Fig. 1: Immunoactive scaffold activates T cells and suppresses Treg cells.
Fig. 2: Engineered scaffolds that curb breast cancer.
Fig. 3: Engineered scaffolds can suppress the growth of local and distant breast tumours and create anti-cancer memory.
Fig. 4: Engineered scaffolds that curb melanoma.
Fig. 5: Engineered scaffolds can suppress the growth of local and distant tumours.
Fig. 6: Engineered scaffolds deliver antigen-specific T cells, suppress Treg cells and control melanomas.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data for the figures, are available from figshare with the identifier https://doi.org/10.6084/m9.figshare.21406713.

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Acknowledgements

We thank L. Bentolila and S. Xu for their technical assistance with confocal imaging and animal imaging studies, respectively, and S. Haile for her assistance with flow cytometry. M.J.B. discloses support in part for the research described in this study from the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center (JCCC). L.-S.B. discloses support in part for the research described in this study from the UCLA CTSI (UL1TR001881). S.L. discloses support in part for the research described in this study from the National Institutes of Health (NIH) (R01 CA234343). F.S.M. discloses support in part for the research described in this study from the R&D fund by Symphony Bioscience. Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory and the Leica Microsystems Centre of Excellence at the California NanoSystems Institute at UCLA, which is supported by funding from the NIH Shared Instrumentation Grant (S10OD025017) and NSF Major Research Instrumentation grant (CHE-0722519). Scanning electron microscopy was performed at California NanoSystems Institute Electron Imaging Centre for NanoMachines Shared Resource Facility at UCLA. Flow cytometry was partially performed at the UCLA JCCC and Centre for AIDS Research Flow Cytometry Core Facility, which are partially supported by NIH (P30 CA016042 and 5P30 AI028697), and by the JCCC, the UCLA AIDS Institute, the David Geffen School of Medicine at UCLA, the UCLA Chancellor’s Office and the UCLA Vice Chancellor’s Office of Research. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIH (United States) or/and other agencies of the State of California.

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Author notes

  1. These authors contributed equally: Fatemeh S. Majedi, Mohammad Mahdi Hasani-Sadrabadi.

Authors and Affiliations

  1. Department of Bioengineering, University of California, Los Angeles, CA, USA

    Fatemeh S. Majedi, Mohammad Mahdi Hasani-Sadrabadi, Song Li & Louis-S. Bouchard

  2. Symphony Biosciences Inc, Los Angeles, CA, USA

    Fatemeh S. Majedi

  3. Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California, Los Angeles, CA, USA

    Timothy J. Thauland & Manish J. Butte

  4. Department of Pediatric Surgery, Texas Children’s Hospital, Houston, TX, USA

    Sundeep G. Keswani

  5. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Louis-S. Bouchard

  6. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA

    Manish J. Butte

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Contributions

F.S.M., M.M.H.-S., L.-S.B., S.L. and M.J.B. conceived and designed the experiments. F.S.M, M.M.H.-S. and T.J.T. performed the experiments. S.G.K. performed terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining. F.S.M, M.M.H.-S. and M.J.B. analysed the data and wrote the manuscript. All authors discussed the results and commented on the manuscript. M.J.B. supervised all work.

Corresponding authors

Correspondence to Fatemeh S. Majedi, Song Li or Manish J. Butte.

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Competing interests

The Regents of the University of California filed patent applications (PCT/US2020/051363 and WO2021055658A1) related to this study, with F.S.M, M.M.H.-S. and M.J.B. as inventors. F.S.M, M.M.H.-S. and M.J.B. are founders and equity holders in Symphony Biosciences. The other authors declare no competing interests.

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Majedi, F.S., Hasani-Sadrabadi, M.M., Thauland, T.J. et al. Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds. Nat. Biomed. Eng 7, 56–71 (2023). https://doi.org/10.1038/s41551-022-00977-0

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