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Induction of T-helper-17-cell-mediated anti-tumour immunity by pathogen-mimicking polymer nanoparticles

Nature Biomedical Engineering volume 7, pages 72–84 (2023)Cite this article

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Abstract

The effectivity of cancer immunotherapies is hindered by immunosuppressive tumour microenvironments that are poorly infiltrated by effector T cells and natural killer cells. In infection and autoimmune disease, the recruitment and activation of effector immune cells is coordinated by pro-inflammatory T helper 17 (TH17) cells. Here we show that pathogen-mimicking hollow nanoparticles displaying mannan (a polysaccharide that activates TH17 cells in microbial cell walls) limit the fraction of regulatory T cells and induce TH17-cell-mediated anti-tumour responses. The nanoparticles activate the pattern-recognition receptor Dectin-2 and Toll-like receptor 4 in dendritic cells, and promote the differentiation of CD4+ T cells into the TH17 phenotype. In mice, intra-tumoural administration of the nanoparticles decreased the fraction of regulatory T cells in the tumour while markedly increasing the fractions of TH17 cells (and the levels of TH17-cell-associated cytokines), CD8+ T cells, natural killer cells and M1-like macrophages. The anti-tumoural activity of the effector cells was amplified by an agonistic antibody against the co-stimulatory receptor OX40 in multiple mouse models. Nanomaterials that induce TH17-cell-mediated immune responses may have therapeutic potential.

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Fig. 1: Mann-NC for cancer immunotherapy.
Fig. 2: Mann-NC activates Dectin-2 and TLR-4 and induces IL-17+ CD4+ T cells.
Fig. 3: Mann-NC activates innate immune cells and TH17 cells and exerts anti-tumour effect.
Fig. 4: Mann-NC induces TH17-associated cytokines and chemokines and promotes CD8+ T-cell and NK cell responses.
Fig. 5: Mann-NC induces TH17-associated cytokines and chemokines and promotes CD8+ T-cell and NK cell responses.
Fig. 6: Mann-NC and αOX40 combination elicits strong immune activation with potent anti-tumour effect.
Fig. 7: Mann-NC and αOX40 combination elicits strong immune activation with potent anti-tumour effect.
Fig. 8: Mann-NC and αOX40 combination exhibits robust anti-tumour efficacy in murine tumour models.

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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 are provided with this paper. All data generated in this study are available from the corresponding authors on reasonable request.

References

  1. Medzhitov, R. & Janeway, C. Jr Innate immunity. N. Engl. J. Med 343, 338–344 (2000).

    Article  CAS  Google Scholar 

  2. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  Google Scholar 

  3. Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009).

    Article  CAS  Google Scholar 

  4. Zou, W. & Restifo, N. P. TH17 cells in tumour immunity and immunotherapy. Nat. Rev. Immunol. 10, 248–256 (2010).

    Article  CAS  Google Scholar 

  5. Noack, M. & Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun. Rev. 13, 668–677 (2014).

    Article  CAS  Google Scholar 

  6. Khader, S. A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).

    Article  CAS  Google Scholar 

  7. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008).

    Article  CAS  Google Scholar 

  8. Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    Article  CAS  Google Scholar 

  9. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  Google Scholar 

  10. Solt, L. A. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011).

    Article  CAS  Google Scholar 

  11. Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).

    Article  CAS  Google Scholar 

  12. Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).

    Article  CAS  Google Scholar 

  13. Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).

    Article  CAS  Google Scholar 

  14. Wilke, C. M., Bishop, K., Fox, D. & Zou, W. Deciphering the role of Th17 cells in human disease. Trends Immunol. 32, 603–611 (2011).

    Article  CAS  Google Scholar 

  15. Knochelmann, H. M. et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell. Mol. Immunol. 15, 458–469 (2018).

    Article  CAS  Google Scholar 

  16. Martin-Orozco, N. et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31, 787–798 (2009).

    Article  CAS  Google Scholar 

  17. Kryczek, I. et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114, 1141–1149 (2009).

    Article  CAS  Google Scholar 

  18. Xie, Y. et al. Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma. J. Exp. Med 207, 651–667 (2010).

    Article  CAS  Google Scholar 

  19. Muranski, P. et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity 35, 972–985 (2011).

    Article  CAS  Google Scholar 

  20. Viaud, S. et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res. 71, 661–665 (2011).

    Article  CAS  Google Scholar 

  21. Si, Y. et al. Adjuvant-free nanofiber vaccine induces in situ lung dendritic cell activation and TH17 responses. Sci. Adv. 6, eaba0995 (2020).

    Article  CAS  Google Scholar 

  22. Robinson, M. J. et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J. Exp. Med. 206, 2037–2051 (2009).

    Article  CAS  Google Scholar 

  23. Saijo, S. et al. Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32, 681–691 (2010).

    Article  CAS  Google Scholar 

  24. Netea, M. G. et al. Variable recognition of Candida albicans strains by TLR4 and lectin recognition receptors. Med Mycol. 48, 897–903 (2010).

    Article  CAS  Google Scholar 

  25. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373 (2010).

    Article  CAS  Google Scholar 

  26. Garcia-Rubio, R., de Oliveira, H. C., Rivera, J. & Trevijano-Contador, N. The fungal cell wall: Candida, Cryptococcus, and Aspergillus species. Front. Microbiol. 10, 2993 (2019).

    Article  Google Scholar 

  27. Son, S. et al. Sugar-nanocapsules imprinted with microbial molecular patterns for mRNA vaccination. Nano Lett. 20, 1499–1509 (2020).

    Article  CAS  Google Scholar 

  28. Pradhan, A. et al. Non-canonical signalling mediates changes in fungal cell wall PAMPs that drive immune evasion. Nat. Commun. 10, 5315 (2019).

    Article  Google Scholar 

  29. Graus, M. S. et al. Mannan molecular substructures control nanoscale glucan exposure in Candida. Cell Rep. 24, 2432–2442.e2435 (2018).

    Article  CAS  Google Scholar 

  30. Croft, M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57–78 (2010).

    Article  CAS  Google Scholar 

  31. Aspeslagh, S. et al. Rationale for anti-OX40 cancer immunotherapy. Eur. J. Cancer 52, 50–66 (2016).

    Article  CAS  Google Scholar 

  32. Korolenko, T. A., Bgatova, N. P. & Vetvicka, V. Glucan and mannan—two peas in a pod. Int J. Mol. Sci. 20, 3189 (2019).

    Article  CAS  Google Scholar 

  33. Vendele, I. et al. Mannan detecting C-type lectin receptor probes recognise immune epitopes with diverse chemical, spatial and phylogenetic heterogeneity in fungal cell walls. PLoS Pathog. 16, e1007927 (2020).

    Article  Google Scholar 

  34. Hou, Y. et al. Co-delivery of antigen and dual adjuvants by aluminum hydroxide nanoparticles for enhanced immune responses. J. Control. Release 326, 120–130 (2020).

    Article  CAS  Google Scholar 

  35. Rennick, J. J., Johnston, A. P. & Parton, R. G. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol. 16, 266–276 (2021).

    Article  CAS  Google Scholar 

  36. Chen, C. & Gao, F.-H. Th17 cells paradoxical roles in melanoma and potential application in immunotherapy. Front. Immunol. 10, 187 (2019).

  37. Ankathatti Munegowda, M., Deng, Y., Mulligan, S. J. & Xiang, J. Th17 and Th17-stimulated CD8+ T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity. Cancer Immunol. Immunother. 60, 1473–1484 (2011).

    Article  Google Scholar 

  38. Shortman, K. & Heath, W. R. The CD8+ dendritic cell subset. Immunological Rev. 234, 18–31 (2010).

    Article  CAS  Google Scholar 

  39. Cerovic, V. et al. Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells. Mucosal Immunol. 8, 38–48 (2015).

    Article  CAS  Google Scholar 

  40. McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat. Immunol. 10, 314–324 (2009).

    Article  CAS  Google Scholar 

  41. Bromley, S. K., Mempel, T. R. & Luster, A. D. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nat. Immunol. 9, 970–980 (2008).

    Article  CAS  Google Scholar 

  42. Xin, L. et al. Commensal microbes drive intestinal inflammation by IL-17-producing CD4+ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2. Proc. Natl Acad. Sci. USA 111, 10672–10677 (2014).

    Article  CAS  Google Scholar 

  43. Huang, A. Y. et al. The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc. Natl Acad. Sci. USA 93, 9730–9735 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Sun, X. et al. Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy. Nat. Nanotechnol. 16, 1260–1270 (2021).

    Article  CAS  Google Scholar 

  46. Zhao, H. & Heindel, N. D. Determination of degree of substitution of formyl groups in polyaldehyde dextran by the hydroxylamine hydrochloride method. Pharm. Res. 8, 400–402 (1991).

    Article  CAS  Google Scholar 

  47. Lutz, M. B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH (R01DE030691, R01DE031951, R01DK125087, R01CA271799, R01NS122536, U01CA210152 and P30CA046592), David Koch-Prostate Cancer Foundation Award in Nanotherapeutics and National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2022R1F1A1075064 and 2022R1A2C1006643). A.S.K. acknowledges financial support from the UM CBTP Training Program (NIH T32GM008353). K.S.P. acknowledges financial support from the UM TEAM Training Program (NIH T32DE007057). We thank the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of MHC-I tetramers; and the University of Michigan Cancer Center Immunology Core for ELISA analysis.

Author information

Author notes

  1. These authors contributed equally: Sejin Son, Jutaek Nam.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA

    Sejin Son, Jutaek Nam, April S. Kim & James J. Moon

  2. Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA

    Sejin Son, Jutaek Nam, April S. Kim, Jinsung Ahn, Kyung Soo Park, May Thazin Phoo & James J. Moon

  3. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Sejin Son, Brett Sherren, Omid C. Farokhzad & Jinjun Shi

  4. Department of Biological Sciences, Inha University, Incheon, Republic of Korea

    Sejin Son

  5. Department of Biological Sciences and Bioengineering, Inha University/Industry-Academia Interactive R&E Center for Bioprocess Innovation, Inha University, Incheon, Republic of Korea

    Sejin Son

  6. College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea

    Jutaek Nam

  7. Department of Biomedical Engineering, Dongguk University, Seoul, Republic of Korea

    Jinsung Ahn & Soo-Hong Lee

  8. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA

    Kyung Soo Park, May Thazin Phoo & James J. Moon

  9. Department of Surgery, University of Michigan, Ann Arbor, MI, USA

    Weiping Zou

  10. Seer, Inc., Redwood City, CA, USA

    Omid C. Farokhzad

  11. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA

    James J. Moon

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Contributions

S.S., J.N. and J.J.M. designed the study. S.S., J.N., A.S.K., K.S.P., M.T.P., J.A. and B.S. performed the experiments. S.S., J.N., W.Z., S.-H.L., J.S., O.C.F. and J.J.M interpreted the data. S.S., J.N. and J.J.M. wrote the paper.

Corresponding authors

Correspondence to Sejin Son or James J. Moon.

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Competing interests

A patent application for particles for the delivery of biomolecules has been filed, with S.S., O.C.F. and J.J.M. as inventors. O.C.F. has financial interests in Selecta Biosciences, Tarveda Therapeutics, and Seer. J.J.M. declares financial interests for board membership, as a paid consultant, for research funding, and/or as equity holder in EVOQ Therapeutics, Saros Therapeutics and Intrinsic Medicine.

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Nature Biomedical Engineering thanks Miodrac Colic, Jeffrey Hubbell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 A schematic illustration of Mann-NC synthesis.

A negatively charged template silica nanoparticle was coated with branched polyethyleneimine (PEI, 25 kDa) polymer in ultra-pure water, followed by a chemical crosslinking step. The surface of PEI-coated silica nanoparticle was reacted with oxidized mannan polymers by the aldehyde-amine reaction. Then the silica nanoparticle core was selectively removed, resulting in hollow Mann-NC entirely composed of mannan polymers.

Extended Data Fig. 2 Phenotype and activity of CD4 T cells induced by Mann-NC.

(a) DCs stimulated by Mann-NC trigger the differentiation of CD4 + T-cells toward Th17 phenotype. BMDCs isolated from BDC2.5 TCR transgenic mice were treated with p31 MHC-II epitope with and without Mann-NC. After overnight incubation, p31-specific CD4 + T-cells from BDC2.5 TCR transgenic mice were added and cultured for 3 days. IL-17A released into the media was measured by ELISA, and CD4 + T-cells expressing IL-17A was measured by intracellular cytokine staining. (b) Mann-NC-inducing OX40 expression levels of Foxp3 + CD4 + T-cells and representative contour plots. (c-f) Tumor-draining lymph nodes were analysed for the frequencies of (c) CD4 + T-cells, (d) IL17 + CD4 + Th17 cells, (e) Foxp3 + CD4 + Tregs, and (f) the corresponding Th17/Treg ratio. (g) CT26 tumor-bearing mice were treated with Mann-NC as in Fig. 3a, and CD4 + T-cells in the TME on day 15 were analysed for their subsets. Data represent mean ± SEM, from a representative experiment (n = 4 (a); n = 7 (b); n = 7 for Native-Mann and Mann-NC, or 8 for PBS on day 15, or 10 for PBS on day 12 (c-f); or n = 8 (g) biologically independent samples) from two (a,b,g) or three (c-f) independent experiments. ***P < 0.001, ****P < 0.0001, analysed by one-way (a) or two-way (c-f) ANOVA with Bonferroni’s multiple comparisons test or unpaired two-tailed Student’s t-test (b, g).

Extended Data Fig. 3 Cellular uptake of Mann-NC among tumor cells and innate immune cells in local tumors.

BALB/c mice were inoculated subcutaneously with 1.5 × 105 CT26 cells on day 0 and treated by intratumoral administration of Cy5.5-Mann-NC on day 9. After 3 days, tumor tissues were analysed for Cy5.5+ cells among CD45- tumor cells, CD11c + DCs, Ly6C+ monocytes, F4/80+ macrophages, and Ly6G+ neutrophils. Data represent mean ± SEM, from a representative experiment with n = 5 biologically independent samples from two independent experiments.

Extended Data Fig. 4 Representative contour plots.

Shown are representative contour plots of IFN-γ + CD8 T-cells, granzyme B + CD8 + T-cells, IFN-γ + NK cells, and granzyme B + NK cells for the dataset shown in the main Fig. 5e-f.

Extended Data Fig. 5 Representative contour plots.

Shown are the representative contour plots of CD80 + CD11c + DCs, CD103 + CD11c + DCs, and CD8𝛼 + CD103 + CD11c + DCs for the dataset shown in the main Fig. 7a.

Extended Data Fig. 6 Immunofluorescence analysis of IL-17A expression.

Immunofluorescence images of IL-17A expression among CD4 T-cells and CD8 T-cells in TME on day 15. Scale bar represents 50 μm.

Extended Data Fig. 7 Immunofluorescence analysis of IFN-γ expression.

Immunofluorescence images of IFN-γ expression among CD4 T-cells and CD8 T-cells in TME on day 15. Scale bar represents 50 μm.

Supplementary information

Source data

Source Data Figs. 3–8

Source data for tumour size.

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Son, S., Nam, J., Kim, A.S. et al. Induction of T-helper-17-cell-mediated anti-tumour immunity by pathogen-mimicking polymer nanoparticles. Nat. Biomed. Eng 7, 72–84 (2023). https://doi.org/10.1038/s41551-022-00973-4

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