Abstract
Immunotherapy holds tremendous promise for improving cancer treatment1. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the ‘abscopal effect’2. Unfortunately, response rates for this strategy remain low3. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
12 February 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41565-021-00864-w
References
Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).
Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).
McNutt, M. Cancer immunotherapy. Science 342, 1417 (2013).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105, 256–265 (2013).
Sharabi, A. B., Lim, M., DeWeese, T. L. & Drake, C. G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16, E498–E509 (2015).
Chan, J. K. et al. Alarmins: awaiting a clinical response. J. Clin. Invest. 122, 2711–2719 (2012).
Curtin, J. F. et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 6, e10 (2009).
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).
Fang, R. H., Kroll, A. V. & Zhang, L. Nanoparticle-based manipulation of antigen-presenting cells for cancer immunotherapy. Small 11, 5483–5496 (2015).
Smith, D. M., Simon, J. K. & Baker, J. R. Jr Applications of nanotechnology for immunology. Nat. Rev. Immunol. 13, 592–605 (2013).
Goldberg, M. S. Immunoengineering: how nanotechnology can enhance cancer immunotherapy. Cell 161, 201–204 (2015).
Irvine, D. J., Hanson, M. C., Rakhra, K. & Tokatlian, T. Synthetic nanoparticles for vaccines and immunotherapy. Chem. Rev. 115, 11109–11146 (2015).
Shao, K. et al. Nanoparticle-based immunotherapy for cancer. ACS Nano 9, 16–30 (2015).
Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015).
Jokerst, J. V., Lobovkina, T., Zare, R. N. & Gambhir, S. S. Nanoparticle PEGylation for imaging and therapy. Nanomedicine 6, 715–728 (2011).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Kardos, J. et al. Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1, e85902 (2016).
Gubin, M. M., Artyomov, M. N., Mardis, E. R. & Schreiber, R. D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin. Invest. 125, 3413–3421 (2015).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).
Bachmann, M. F. & Jennings, G. T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787–796 (2010).
Wang, C., Sun, W., Wright, G, Wang, A. Z. & Gu, Z. Inflammation-triggered cancer immunotherapy by programmed delivery of CpG and anti-PD1 antibody. Adv. Mater. 28, 8912–8920 (2016).
Melief, C. J., van Hall, T., Arens, R., Ossendorp, F. & van der Burg, S. H. Therapeutic cancer vaccines. J. Clin. Invest. 125, 3401–3412 (2015).
Govender, T., Stolnik, S., Garnett, M. C., Illum, L. & Davis, S. S. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J. Control Release 57, 171–185 (1999).
Zhang, L. et al. Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform. ACS Nano 2, 1696–1702 (2008).
Wisniewski, J. R., Zougman, A., Nagaraj, N. & Mann, M. Universal sample preparation method for proteome analysis. Nat. Methods 6, 359–362 (2009).
Vizcaino, J. A. et al. 2016 Update of the PRIDE database and its related tools. Nucleic Acids Res. 44, 11033 (2016).
Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).
Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).
Martinov, T. & Fife, B. T. Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies. Ann. Transl. Med. 4, 82 (2016).
Acknowledgements
The authors acknowledge D. Smalley at the Michael Hooker Proteomics Center for her assistance with mass spectrum data analysis (CA016086). The authors also acknowledge the University of North Carolina (UNC) Flow Cytometry Core Facility (P30 CA016086). The authors also thank our funding sources. A.Z.W., J.E.T., S.T. and J.M.D. are supported by funding from the National Institutes of Health (NIH)/National Cancer Institute (NCI) (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence (CCNE) Nano Approaches to Modulate Host Cell Response for Cancer Therapy). B.V. is supported by funding from the UNC University Cancer Research Fund, Paul Calabresi Oncology K12 Award and a UNC CCNE Pilot Grant. A.Z.W. is also supported by funding from the NIH/NCI (U54 CA151652 and R01 CA178748) for this work. A.Z.W. was also supported by funding from the NIH/NCI (R21 CA182322). This work was also supported by a generous gift from E. and M. Barclay.
Author information
Authors and Affiliations
Contributions
A.Z.W. and T.Z. conceived and designed the experiments with Y.M. and K.C.R. Y.M. and M.J.E. performed the efficacy study. Y.M. also performed the mechanistic study with the help of S.T. and K.P.M. L.H. processed all the raw mass spectrometry data. S.C. and B.G.V. analysed the mass spectrometry data for neoantigens. All authors analysed and discussed the data. A.Z.W., Y.M. and K.C.R. wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary information
Supplementary information (PDF 2610 kb)
Rights and permissions
About this article
Cite this article
Min, Y., Roche, K., Tian, S. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nature Nanotech 12, 877–882 (2017). https://doi.org/10.1038/nnano.2017.113
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nnano.2017.113
This article is cited by
-
Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy
Journal of Hematology & Oncology (2024)
-
Small-molecule-mediated control of the anti-tumour activity and off-tumour toxicity of a supramolecular bispecific T cell engager
Nature Biomedical Engineering (2024)
-
Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination
Nature Nanotechnology (2024)
-
GM-CSF augmented the photothermal immunotherapeutic outcome of self-driving gold nanoparticles against a mouse CT-26 colon tumor model
Biomaterials Research (2023)
-
Multifunctional nanoplatforms application in the transcatheter chemoembolization against hepatocellular carcinoma
Journal of Nanobiotechnology (2023)