Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy

Nature Nanotechnology volume 15, pages 1043–1052 (2020)Cite this article

Subjects

Abstract

Cancer metastases and recurrence after surgical resection remain an important cause of treatment failure. Here we demonstrate a general strategy to fabricate personalized nanovaccines based on a cationic fluoropolymer for post-surgical cancer immunotherapy. Nanoparticles formed by mixing the fluoropolymer with a model antigen ovalbumin, induce dendritic cell maturation via the Toll-like receptor 4 (TLR4)-mediated signalling pathway, and promote antigen transportation into the cytosol of dendritic cells, which leads to an effective antigen cross-presentation. Such a nanovaccine inhibits established ovalbumin-expressing B16-OVA melanoma. More importantly, a mix of the fluoropolymer with cell membranes from resected autologous primary tumours synergizes with checkpoint blockade therapy to inhibit post-surgical tumour recurrence and metastases in two subcutaneous tumour models and an orthotopic breast cancer tumour. Furthermore, in the orthotopic tumour model, we observed a strong immune memory against tumour rechallenge. Our work offers a simple and general strategy for the preparation of personalized cancer vaccines to prevent post-operative cancer recurrence and metastasis.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Preparation, characterization and DC activation of nanovaccines.
Fig. 2: In vitro DC activation by nanovaccines.
Fig. 3: In vivo immune stimulation by F-PEI/OVA nanovaccines.
Fig. 4: F13-PEI/OVA nanovaccine inhibits tumour growth and prolongs survival in tumour-bearing mice.
Fig. 5: F13-PEI/Mem nanovaccine synergy with ICB therapies to treat distant tumours post-surgery.
Fig. 6: F13-PEI/Mem nanovaccine synergy with ICB therapy and the long-term memory immune response to treat orthotopic 4T1 tumours post-surgery.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and Supplementary Information. 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 authors upon reasonable request.

References

  1. Klevorn, L. E. & Teague, R. M. Adapting cancer immunotherapy models for the real world. Trends Immunol. 37, 354–363 (2016).

    Article  CAS  Google Scholar 

  2. Littman, D. R. Releasing the brakes on cancer immunotherapy. Cell 162, 1186–1190 (2015).

    Article  CAS  Google Scholar 

  3. Wang, C., Ye, Y., Hu, Q., Bellotti, A. & Gu, Z. Tailoring biomaterials for cancer immunotherapy: emerging trends and future outlook. Adv. Mater. 29, 1606036 (2017).

    Article  Google Scholar 

  4. Lu, J. et al. Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. Nat. Commun. 8, 1811 (2017).

    Article  Google Scholar 

  5. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    Article  CAS  Google Scholar 

  6. Chao, Y. et al. Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses. Nat. Biomed. Eng. 2, 611–621 (2018).

    Article  CAS  Google Scholar 

  7. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    Article  CAS  Google Scholar 

  8. Chen, Q. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat. Nanotechnol. 14, 89–97 (2019).

    Article  CAS  Google Scholar 

  9. Wang, C. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat. Biomed. Eng. 1, 0011 (2017).

    Article  CAS  Google Scholar 

  10. Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    Article  CAS  Google Scholar 

  11. Yarchoan, M., Johnson, B. A. III, Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).

    Article  CAS  Google Scholar 

  12. Guo, Y., Lei, K. & Tang, L. Neoantigen vaccine delivery for personalized anticancer immunotherapy. Front. Immunol. 9, 1499 (2018).

    Article  Google Scholar 

  13. Zhu, G., Zhang, F., Ni, Q., Niu, G. & Chen, X. Efficient nanovaccine delivery in cancer immunotherapy. ACS Nano 11, 2387–2392 (2017).

    Article  CAS  Google Scholar 

  14. Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 12, 648–654 (2017).

    Article  CAS  Google Scholar 

  15. Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat. Mater. 16, 489–496 (2016).

    Article  Google Scholar 

  16. Rodriguez, A., Regnault, A., Kleijmeer, M., Ricciardi-Castagnoli, P. & Amigorena, S. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nat. Cell Biol. 1, 362–368 (1999).

    Article  CAS  Google Scholar 

  17. Cruz, F. M., Colbert, J. D., Merino, E., Kriegsman, B. A. & Rock, K. L. The biology and underlying mechanisms of cross-presentation of exogenous antigens on MHC-I molecules. Annu. Rev. Immunol. 35, 149–176 (2017).

    Article  CAS  Google Scholar 

  18. Lv, S. et al. Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection. Hepatology 59, 385–394 (2014).

    Article  CAS  Google Scholar 

  19. Yang, J., Zhang, Q., Chang, H. & Cheng, Y. Surface-engineered dendrimers in gene delivery. Chem. Rev. 115, 5274–5300 (2015).

    Article  CAS  Google Scholar 

  20. Zhang, Z. et al. The fluorination effect of fluoroamphiphiles in cytosolic protein delivery. Nat. Commun. 9, 1377 (2018).

    Article  Google Scholar 

  21. Cametti, M., Crousse, B., Metrangolo, P., Milani, R. & Resnati, G. The fluorous effect in biomolecular applications. Chem. Soc. Rev. 41, 31–42 (2012).

    Article  CAS  Google Scholar 

  22. Stewart, M. P., Langer, R. & Jensen, K. F. Intracellular delivery by membrane disruption: mechanisms, strategies, and concepts. Chem. Rev. 118, 7409–7531 (2018).

    Article  CAS  Google Scholar 

  23. Janeway, C. A. Jr & Bottomly, K. Signals and signs for lymphocyte responses. Cell 76, 275–285 (1994).

    Article  CAS  Google Scholar 

  24. Folks, T. M. et al. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc. Natl Acad. Sci. USA 86, 2365–2368 (1989).

    Article  CAS  Google Scholar 

  25. Dienz, O. & Rincon, M. The effects of IL-6 on CD4 T cell responses. Clin. Immunol. 130, 27–33 (2009).

    Article  CAS  Google Scholar 

  26. Lanzavecchia, A. & Sallusto, F. Regulation of T cell immunity by dendritic cells. Cell 106, 263–266 (2001).

    Article  CAS  Google Scholar 

  27. He, W. et al. Re-polarizing myeloid-derived suppressor cells (MDSCs) with cationic polymers for cancer immunotherapy. Sci. Rep. 6, 24506 (2016).

    Article  CAS  Google Scholar 

  28. Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856 (2008).

    Article  CAS  Google Scholar 

  29. Yamamoto, A. et al. Bafilomycin A prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 23, 33–42 (1998).

    Article  CAS  Google Scholar 

  30. Wang, M., Liu, H., Li, L. & Cheng, Y. A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios. Nat. Commun. 5, 3053 (2014).

    Article  Google Scholar 

  31. Bevan, M. J. Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4, 595–602 (2004).

    Article  CAS  Google Scholar 

  32. Yang, R. et al. Cancer cell membrane-coated adjuvant nanoparticles with mannose modification for effective anticancer vaccination. ACS Nano 12, 5121–5129 (2018).

    Article  CAS  Google Scholar 

  33. Kroll, A. V. et al. Nanoparticulate delivery of cancer cell membrane elicits multiantigenic antitumor immunity. Adv. Mater. 29, 1703969 (2017).

    Article  Google Scholar 

  34. Ochyl, L. J. et al. PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials 182, 157–166 (2018).

    Article  CAS  Google Scholar 

  35. Grosso, J. F. & Jure-Kunkel, M. N. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immunol. Res. 13, 5 (2013).

    Google Scholar 

  36. D’Alise, A. M. et al. Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade. Nat. Commun. 10, 2688 (2019).

    Article  Google Scholar 

  37. Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mater. 17, 528–534 (2018).

    Article  CAS  Google Scholar 

  38. Xu, L. et al. Morphologically virus-like fullerenol nanoparticles act as the dual-functional nanoadjuvant for HIV-1 vaccine. Adv. Mater. 25, 5928–5936 (2013).

    Article  CAS  Google Scholar 

  39. Issadore, D. et al. Self-assembled magnetic filter for highly efficient immunomagnetic separation. Lab Chip 11, 147–151 (2011).

    Article  CAS  Google Scholar 

  40. Xu, J. et al. Near-infrared-triggered photodynamic therapy with multitasking upconversion nanoparticles in combination with checkpoint blockade for immunotherapy of colorectal cancer. ACS Nano 11, 4463–4474 (2017).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by the National Key Research and Development (R&D) Program of China (2016YFA0201200, 2017YFE0131700 and 2019YFA0904500), the National Natural Science Foundation of China (51525203, 21725402 and 51761145041), the 111 Project, the Jiangsu Social Development Project (BE2019658), the Natural Science Foundation of Jiangsu Higher Education Institutions of China (19KJA310008) and the Collaborative Innovation Center of Suzhou Nano Science and Technology (Nano-CIC). The authors thank H. Liu for B16-OVA tumour cells and X. Wang for the OT-I mice. Our gratitude also goes to Y. Huang for valuable comments and suggestions.

Author information

Authors and Affiliations

  1. Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, China

    Jun Xu, Qi Zhuang, Zongjin Yang, Zhiqin Cao, Ligeng Xu, Chenya Wang, Hanfei Wu, Ziliang Dong, Yu Chao, Chao Wang, Rui Peng & Zhuang Liu

  2. South China Advanced Institute for Soft Matter Science and Technology, South China University of Technology, Guangzhou, China

    Jia Lv & Yiyun Cheng

  3. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China

    Pei Pei & Kai Yang

  4. Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China

    Yiyun Cheng

Authors
  1. Jun Xu
    View author publications

    Search author on:PubMed Google Scholar

  2. Jia Lv
    View author publications

    Search author on:PubMed Google Scholar

  3. Qi Zhuang
    View author publications

    Search author on:PubMed Google Scholar

  4. Zongjin Yang
    View author publications

    Search author on:PubMed Google Scholar

  5. Zhiqin Cao
    View author publications

    Search author on:PubMed Google Scholar

  6. Ligeng Xu
    View author publications

    Search author on:PubMed Google Scholar

  7. Pei Pei
    View author publications

    Search author on:PubMed Google Scholar

  8. Chenya Wang
    View author publications

    Search author on:PubMed Google Scholar

  9. Hanfei Wu
    View author publications

    Search author on:PubMed Google Scholar

  10. Ziliang Dong
    View author publications

    Search author on:PubMed Google Scholar

  11. Yu Chao
    View author publications

    Search author on:PubMed Google Scholar

  12. Chao Wang
    View author publications

    Search author on:PubMed Google Scholar

  13. Kai Yang
    View author publications

    Search author on:PubMed Google Scholar

  14. Rui Peng
    View author publications

    Search author on:PubMed Google Scholar

  15. Yiyun Cheng
    View author publications

    Search author on:PubMed Google Scholar

  16. Zhuang Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Z.L., Y.C., R.P. and J.X. conceived the project and designed the experiments. Z.L. and R.P. supervised the project. Z.L., R.P. and J.X. wrote the manuscript. J.X., J.L., Q.Z., Z.Y., Z.C., P.P., C.W., H.W., Z.D. and Y.C. carried out the experiments. J.L. assisted in taking and analysing the microscope images. C.W. and K.Y. supported the operation and analysis of the flow cytometer. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Rui Peng, Yiyun Cheng or Zhuang Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Nanotechnology thanks Jeffrey Hubbell, Helder A. Santos and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–27 and Tables 1 and 2.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, J., Lv, J., Zhuang, Q. et al. A general strategy towards personalized nanovaccines based on fluoropolymers for post-surgical cancer immunotherapy. Nat. Nanotechnol. 15, 1043–1052 (2020). https://doi.org/10.1038/s41565-020-00781-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-020-00781-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research