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Metabolic labeling and targeted modulation of dendritic cells

Nature Materials volume 19, pages 1244–1252 (2020)Cite this article

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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.

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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.

References

  1. Laughlin, S. T. & Bertozzi, C. R. Metabolic labeling of glycans with azido sugars and subsequent glycan-profiling and visualization via staudinger ligation. Nat. Protoc. 2, 2930 (2007).

    CAS  Google Scholar 

  2. Laughlin, S. T. et al. Metabolic labeling of glycans with azido sugars for visualization and glycoproteomics. Methods Enzymol. 415, 230–250 (2006).

    CAS  Google Scholar 

  3. Chang, P. V. et al. Copper-free click chemistry in living animals. Proc. Natl Acad. Sci. USA 107, 1821–1826 (2010).

    CAS  Google Scholar 

  4. Baskin, J. M. et al. Copper-free click chemistry for dynamic in vivo imaging. Proc. Natl Acad. Sci. USA 104, 16793–16797 (2007).

    CAS  Google Scholar 

  5. Wang, H. et al. Targeted ultrasound-assisted cancer-selective chemical labeling and subsequent cancer imaging using click chemistry. Angew. Chem. Int. Ed. 55, 5452–5456 (2016).

    CAS  Google Scholar 

  6. Wang, H. et al. In vivo cancer targeting via glycopolyester nanoparticle mediated metabolic cell labeling followed by click reaction. Biomaterials 218, 119305 (2019).

    CAS  Google Scholar 

  7. Lee, S. et al. Chemical tumor-targeting of nanoparticles based on metabolic glycoengineering and click chemistry. ACS Nano 8, 2048–2063 (2014).

    CAS  Google Scholar 

  8. Du, L., Qin, H., Ma, T., Zhang, T. & Xing, D. In vivo imaging-guided photothermal/photoacoustic synergistic therapy with bioorthogonal metabolic glycoengineering-activated tumor targeting nanoparticles. ACS Nano 11, 8930–8943 (2017).

    CAS  Google Scholar 

  9. Li, X., Xu, X., Rao, X., Tian, Y. & Yi, W. Chemical remodeling cell surface glycans for immunotargeting of tumor cells. Carbohydr. Res. 452, 25–34 (2017).

    CAS  Google Scholar 

  10. Le Gall, C. M., Weiden, J., Eggermont, L. J. & Figdor, C. G. Dendritic cells in cancer immunotherapy. Nat. Mater. 17, 474–475 (2018).

    Google Scholar 

  11. Sallusto, F. et al. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 29, 1617–1625 (1999).

    CAS  Google Scholar 

  12. Liu, Y.-J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259–262 (2001).

    CAS  Google Scholar 

  13. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    CAS  Google Scholar 

  14. De Vries, I. J. M. et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat. Biotechnol. 23, 1407–1413 (2005).

    Google Scholar 

  15. Rhee, I., Zhong, M.-C., Reizis, B., Cheong, C. & Veillette, A. Control of dendritic cell migration, T cell-dependent immunity, and autoimmunity by protein tyrosine phosphatase PTPN12 expressed in dendritic cells. Mol. Cell Biol. 34, 888–899 (2014).

    Google Scholar 

  16. Ahrens, E. T. & Bulte, J. W. Tracking immune cells in vivo using magnetic resonance imaging. Nat. Rev. Immunol. 13, 755–763 (2013).

    CAS  Google Scholar 

  17. Bertozzi, C. R. & Kiessling, L. Chemical glycobiology. Science 291, 2357–2364 (2001).

    CAS  Google Scholar 

  18. Luchansky, S. J. et al. in Methods of Enzymology Vol. 362 (eds Lee Yuan, C. & Lee Reiko, T.) 249–272 (Academic Press, 2003).

  19. Prescher, J. A. & Bertozzi, C. R. Chemistry in living systems. Nat. Chem. Biol. 1, 13–21 (2005).

    CAS  Google Scholar 

  20. Kang, S.-W. et al. Cell labeling and tracking method without distorted signals by phagocytosis of macrophages. Theranostics 4, 420–431 (2014).

    Google Scholar 

  21. Verbeke, C. S. & Mooney, D. J. Injectable, pore-forming hydrogels for in vivo enrichment of immature dendritic cells. Adv. Healthc. Mater. 4, 2677–2687 (2015).

    CAS  Google Scholar 

  22. Verbeke, C. S. et al. Multicomponent injectable hydrogels for antigen-specific tolerogenic immune modulation. Adv. Healthc. Mater. 6, https://doi.org/10.1002/adhm.201600773 (2017).

  23. Wang, H. et al. In vivo targeting of metabolically labeled cancers with ultra-small silica nanoconjugates. Theranostics 6, 1467–1476 (2016).

    CAS  Google Scholar 

  24. Kearney, C. J. et al. Switchable release of entrapped nanoparticles from alginate hydrogels. Adv. Healthc. Mater. 4, 1634–1639 (2015).

    CAS  Google Scholar 

  25. Kamath, A. T., Henri, S., Battye, F., Tough, D. F. & Shortman, K. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100, 1734–1741 (2002).

    CAS  Google Scholar 

  26. Randolph, G. J., Angeli, V. & Swartz, M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 5, 617–628 (2005).

    CAS  Google Scholar 

  27. Wang, H. et al. Selective in vivo metabolic cell-labeling-mediated cancer targeting. Nat. Chem. Biol. 13, 415–424 (2017).

    CAS  Google Scholar 

  28. Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11–22 (2004).

    CAS  Google Scholar 

  29. Motzer, R. J. et al. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J. Clin. Oncol. 18, 1928–1935 (2000).

    CAS  Google Scholar 

  30. Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6, 595–601 (2006).

    CAS  Google Scholar 

  31. Sato, N., Patel, H. J., Waldmann, T. A. & Tagaya, Y. The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc. Natl Acad. Sci. USA 104, 588–593 (2007).

    CAS  Google Scholar 

  32. Stoklasek, T. A., Schluns, K. S. & Lefrançois, L. Combined IL-15/IL-15Rα immunotherapy maximizes IL-15 activity in vivo. J. Immunol. 177, 6072–6080 (2006).

    CAS  Google Scholar 

  33. Ferlazzo, G. et al. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc. Natl Acad. Sci. USA 101, 16606–16611 (2004).

    CAS  Google Scholar 

  34. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    CAS  Google Scholar 

  35. Epardaud, M. et al. Interleukin-15/Interleukin-15Rα complexes promote destruction of established tumors by reviving tumor-resident CD8+ T Cells. Cancer Res. 68, 2972–2983 (2008).

    CAS  Google Scholar 

  36. Bonifaz, L. C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).

    CAS  Google Scholar 

  37. Tacken, P. J., de Vries, I. J. M., Torensma, R. & Figdor, C. G. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat. Rev. Immunol. 7, 790–802 (2007).

    CAS  Google Scholar 

  38. Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    CAS  Google Scholar 

  39. Reddy, S. T., Rehor, A., Schmoekel, H. G., Hubbell, J. A. & Swartz, M. A. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J. Control. Release 112, 26–34 (2006).

    CAS  Google Scholar 

  40. Tomura, M. et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein ‘Kaede’ transgenic mice. Proc. Natl Acad. Sci. USA 105, 10871–10876 (2008).

    CAS  Google Scholar 

  41. Tomura, M. et al. Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes. Sci. Rep. 4, 6030 (2014).

    CAS  Google Scholar 

  42. Alvarez, D., Vollmann, E. H. & von Andrian, U. H. Mechanisms and consequences of dendritic cell migration. Immunity 29, 325–342 (2008).

    CAS  Google Scholar 

  43. Ichihashi, M. et al. UV-induced skin damage. Toxicology 189, 21–39 (2003).

    CAS  Google Scholar 

  44. Chang, P. V., Dube, D. H., Sletten, E. M. & Bertozzi, C. R. A strategy for the selective imaging of glycans using caged metabolic precursors. J. Am. Chem. Soc. 132, 9516–9518 (2010).

    CAS  Google Scholar 

  45. Hanson, M. C. et al. Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants. J. Clin. Invest. 125, 2532–2546 (2015).

    Google Scholar 

  46. Mueller, S. N., Tian, S. & DeSimone, J. M. Rapid and persistent delivery of antigen by lymph node targeting PRINT nanoparticle vaccine carrier to promote humoral immunity. Mol. Pharm. 12, 1356–1365 (2015).

    CAS  Google Scholar 

  47. Wang, Q., Cao, W., Yang, Z.-G. & Zhao, G.-F. DC targeting DNA vaccines induce protective and therapeutic antitumor immunity in mice. Int. J. Clin. Exp. Med. 8, 17565–17577 (2015).

    CAS  Google Scholar 

  48. Cruz, L. J. et al. Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8+ T cell response: a comparative study. J. Control. Release 192, 209–218 (2014).

    CAS  Google Scholar 

  49. Cheong, C. et al. Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody. Blood 116, 3828–3838 (2010).

    CAS  Google Scholar 

  50. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    CAS  Google Scholar 

  51. Wang, H. & Mooney, D. J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nat. Mater. 17, 761–772 (2018).

    CAS  Google Scholar 

  52. Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).

    CAS  Google Scholar 

  53. Hodi, F. S. Dendritic cell activating scaffold in melanoma. ClinicalTrials.org https://clinicaltrials.gov/show/nct01753089 (2017).

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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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Authors and Affiliations

  1. Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Hua Wang, Miguel C. Sobral, David K. Y. Zhang, Aileen Weiwei Li, Maxence O. Dellacherie, Christina M. Tringides, Sandeep T. Koshy & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Cambridge, MA, USA

    Hua Wang, Miguel C. Sobral, David K. Y. Zhang, Aileen Weiwei Li, Maxence O. Dellacherie, Sandeep T. Koshy & David J. Mooney

  3. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA

    Adam N. Cartwright & Kai W. Wucherpfennig

  4. Harvard Medical School, Boston, MA, USA

    Adam N. Cartwright & Kai W. Wucherpfennig

  5. Harvard Program in Biophysics, Harvard University, Cambridge, MA, USA

    Christina M. Tringides

  6. Harvard–MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Christina M. Tringides

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Contributions

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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