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Metabolic labeling and targeted modulation of dendritic cells

Abstract

Targeted immunomodulation of dendritic cells (DCs) in vivo will enable manipulation of T-cell priming and amplification of anticancer immune responses, but a general strategy has been lacking. Here we show that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time. Azido-labelled DCs were detected in lymph nodes for weeks, and could covalently capture dibenzocyclooctyne (DBCO)-bearing antigens and adjuvants via efficient Click chemistry for improved antigen-specific CD8+ T-cell responses and antitumour efficacy. We also show that azido labelling of DCs allowed for in vitro and in vivo conjugation of DBCO-modified cytokines, including DBCO–IL-15/IL-15Rα, to improve priming of antigen-specific CD8+ T cells. This DC labelling and targeted modulation technology provides an unprecedented strategy for manipulating DCs and regulating DC–T-cell interactions in vivo.

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Fig. 1: Strategy for DC labelling and targeting in vivo.
Fig. 2: Azido-sugar NPs metabolically label DCs, and show on-demand release from gels.
Fig. 3: G400 NP-containing gels recruit and metabolically label DCs with azido groups in vivo.
Fig. 4: Azido-labelled DCs mediate targeted conjugation of DBCO-molecules via Click chemistry.
Fig. 5: Azido labelling of DCs mediates targeted delivery of DBCO-antigens and DBCO-adjuvants, which generates potent cellular immune responses.

Data availability

All data supporting the results are provided with the manuscript. Raw datasets are available at https://dataverse.harvard.edu/privateurl.xhtml?token=4d292632-f627-4a56-8e01-60e36d0883f5.

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Acknowledgements

We acknowledge funding from the National Institutes of Health (grant nos. U01 CA214369 and R01 CA223255). H.W. gratefully acknowledges funding support from the Wyss Technology Development Fellowship. M.C.S. and C.M.T. acknowledge funding support from the Graduate Research Fellowship Program from the National Science Foundation. D.K.Y.Z. acknowledges support from the Canadian Institutes of Health Research. We thank A. J. Najibi at Harvard University for discussions.

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H.W. and D.J.M. conceived the study, designed the experiments and wrote the manuscript. H.W., M.C.S., D.K.Y.Z., A.N.C., A.W.L., M.O.D., C.M.T. and S.K. carried out the experiments. K.W.W. designed IL-15/IL-15R𝛂 and contributed to the design of IL-15/IL-15R𝛂 study.

Corresponding author

Correspondence to David J. Mooney.

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Competing interests

D.J.M. conducts research sponsored by Novartis, Merck, Decibel and Amgen. D.J.M. consults for Agnovos and the Samyang Corporation. D.J.M. holds equity in Immulus. H.W. and D.J.M. are inventors of a patent application on the labelling technology.

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Wang, H., Sobral, M.C., Zhang, D.K.Y. et al. Metabolic labeling and targeted modulation of dendritic cells. Nat. Mater. 19, 1244–1252 (2020). https://doi.org/10.1038/s41563-020-0680-1

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