mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma
Open accessAbstract
We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in the lymph nodes after subcutaneous administration. The calcium phosphate core allowed acid-mediated dissolution in the endo-lysosomal compartment, which prompted rapid release of cargoes after cellular internalization of NP. LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma. The immune responses efficaciously inhibited the melanoma growth. Moreover, co-delivery of PD-L1 siRNA and mRNA vaccine resulted in the downregulation of PD-L1 in the DCs that presented tumor antigens, significantly prompting T cell activation and proliferation. The enhanced T cell response had a profound inhibitory effect on tumor growth and metastasis. Generally, the work provided a paradigm for the development of an mRNA vaccine carrier to boost the anticancer immune response.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mannose-modified lipid nanoparticle-mRNA formulations are preferentially taken up by dendritic cells.
“To further improve vaccine efficacy, APC uptake and T cell activation can be optimized; for example, mannose-modified lipid nanoparticle–mRNA formulations are preferentially taken up by dendritic cells150,201,202.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [202]
Wang et al. generated a nanoparticle system consisting of a pre-condensed core of mRNA and calcium phosphate, stabilized by DOPA and coated by a lipid shell of DOTAP and DSPE-PEG.
“To give an example of an optimized mRNA LNP for lymphatic transport, Wang et al. generated a nanoparticle system consisting of a pre-condensed core of mRNA and calcium phosphate, stabilized by DOPA and coated by a lipid shell of DOTAP and DSPE-PEG [135].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [135]
These mRNA nanoparticles have a relatively small particle size (<50 nm) and an uncharged, strongly PEGylated outer surface.
“These mRNA nanoparticles had a relatively small particle size (<50 nm), and an uncharged, strongly PEGylated outer-surface.”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [135]
Accumulating pre-clinical evidence shows that T cell responses and antitumor effects evoked by mRNA cancer therapeutics can strongly be strengthened by combining them with checkpoint inhibitors, such as anti-PD-1(L)- and anti-CTLA-4 antibodies.
“Indeed, accumulating pre-clinical evidence shows that T cell responses and antitumor effects evoked by mRNA cancer therapeutics can strongly be strengthened by combining them with checkpoint inhibitors, such as anti-PD-1(L)-, and also anti-CTLA-4 antibodies [135,196,214,218,219].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [135]
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · see citing works
Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001) · Nature · doi:10.1038/35099560 · Cited by 6,129 · see citing works
Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L. J., Malenkovich, N., Okazaki, T., Byrne, M. C., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.7.1027 · Cited by 5,294 · see citing works
Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., & Reis e Sousa, C. (2004) · Science · doi:10.1126/science.1093616 · Cited by 3,444 · see citing works
Brahmer, J. R., Drake, C. G., WOLLNER, I. S., Powderly, J. D., Picus, J., Sharfman, W. H., Stankevich, E., Pons, A., Salay, T. M., McMiller, T. L., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7609 · Cited by 2,967 · see citing works
Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.012 · Cited by 2,662 · see citing works
5'-Triphosphate RNA Is the Ligand for RIG-I
Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., et al. (2006) · Science · doi:10.1126/science.1132505 · Cited by 2,474 · see citing works
Couzin-Frankel, J. (2013) · Science · doi:10.1126/science.342.6165.1432 · Cited by 2,051 · see citing works
Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0830997100 · Cited by 1,006 · see citing works
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
Fife, B. T., Pauken, K. E., Eagar, T. N., Kangas, T. O., Wu, J. Q., Tang, Q., Azuma, M., Krummel, M. F., & Bluestone, J. A. (2009) · Nature Immunology · doi:10.1038/ni.1790 · Cited by 759 · see citing works
Mechanisms of Action of Adjuvants
Awate, S., Babiuk, L. A., & Mutwiri, G. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00114 · Cited by 741 · see citing works
Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
Kormann, M. S. D., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1733 · Cited by 733 · see citing works
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy
Oberli, M. A., Reichmuth, A. M., Dorkin, J. R., Mitchell, M. J., Fenton, O. S., Jaklenec, A., Anderson, D. G., Langer, R., & Blankschtein, D. (2017) · Nano Letters · doi:10.1021/acs.nanolett.6b03329 · Cited by 719 · see citing works
Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation
Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Karikó, K. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq347 · Cited by 682 · see citing works
Blank, C. U., Gajewski, T. F., & Mackensen, A. (2004) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-004-0593-x · Cited by 634 · see citing works
Latchman, Y. E., Liang, S. C., Wu, Y., Chernova, T., Sobel, R. A., Klemm, M., Kuchroo, V. K., Freeman, G. J., & Sharpe, A. H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307252101 · Cited by 631 · see citing works
Thess, A., Grund, S., Mui, B. L., Hope, M. J., Baumhof, P., Fotin-Mleczek, M., & Schlake, T. (2015) · Molecular Therapy · doi:10.1038/mt.2015.103 · Cited by 513 · see citing works
Nakanishi, J., Wada, Y., Matsumoto, K., Azuma, M., Kikuchi, K., & Ueda, S. (2007) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-006-0266-z · Cited by 473 · see citing works
Weide, B., Pascolo, S., Scheel, B., Derhovanessian, E., Pflugfelder, A., Eigentler, T. K., Pawelec, G., Hoerr, I., Rammensee, H.-G., & Garbe, C. (2009) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181a00068 · Cited by 378 · cited 1× · see citing works
“As was often observed in the clinical studies of mRNA vaccine, adjuvant such as GM-CSF was administered with mRNA antigen to boost the immune response.(4,7) Although single-stranded RNA with several structure features could activate various RNA sensors, such as Tolllike receptor, RIG-I, and PKR,(15,16,36) to potentiat…”
Fotin-Mleczek, M., Duchardt, K. M., Lorenz, C., Pfeiffer, R., Ojkić-Zrna, S., Probst, J., & Kallen, K.-J. (2011) · Journal of Immunotherapy · doi:10.1097/cji.0b013e3181f7dbe8 · Cited by 335 · see citing works
Li, J., Yang, Y., & Huang, L. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.10.020 · Cited by 307 · see citing works
Self-citationKübler, H., Scheel, B., Gnad-Vogt, U., Miller, K., Schultze-Seemann, W., vom Dorp, F., Parmiani, G., Hampel, C., Wedel, S., Trojan, L., et al. (2015) · Journal for Immunotherapy of Cancer · doi:10.1186/s40425-015-0068-y · Cited by 287 · see citing works
Xu, Z., Wang, Y., Zhang, L., & Huang, L. (2014) · ACS Nano · doi:10.1021/nn500216y · Cited by 284 · see citing works
Self-citationB7-H1 pathway and its role in the evasion of tumor immunity
Dong, H., & Chen, L. (2003) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0430-2 · Cited by 276 · see citing works
Results of the First Phase I/II Clinical Vaccination Trial With Direct Injection of mRNA
Weide, B., Carralot, J.-P., Reese, A., Scheel, B., Eigentler, T. K., Hoerr, I., Rammensee, H.-G., Garbe, C., & Pascolo, S. (2008) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31815ce501 · Cited by 261 · see citing works
Rittig, S. M., Haentschel, M., Weimer, K. J., Heine, A., Muller, M. R., Brugger, W., Horger, M. S., Maksimovic, O., Stenzl, A., Hoerr, I., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2010.289 · Cited by 226 · see citing works
5’-triphosphate-dependent activation of PKR by RNAs with short stem-loops
Nallagatla, S. R., Hwang, J., Toroney, R., Zheng, X., Cameron, C. E., & Bevilacqua, P. C. (2007) · Science · doi:10.1126/science.1147347 · Cited by 222 · see citing works
Xu, Z., Ramishetti, S., Tseng, Y.-C., Guo, S., Wang, Y., & Huang, L. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.08.021 · Cited by 219 · see citing works
Self-citationWang, Y.-H., Su, H.-H., Yang, Y., Hu, Y.-X., Zhang, L., Blancafort, P., & Huang, L. (2013) · Molecular Therapy · doi:10.1038/mt.2012.250 · Cited by 189 · see citing works
Self-citationCzerniecki, B. J., Carter, C., Rivoltini, L., Koski, G. K., Kim, H. I., Weng, D. E., Roros, J. G., Hijazi, Y. M., Xu, S., Rosenberg, S. A., et al. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.8.3823 · Cited by 185 · see citing works
Udhayakumar, V. K., De Beuckelaer, A., McCaffrey, J., McCrudden, C. M., Kirschman, J. L., Vanover, D., Van Hoecke, L., Roose, K., Deswarte, K., De Geest, B. G., et al. (2017) · Advanced Healthcare Materials · doi:10.1002/adhm.201601412 · Cited by 169 · cited 2× · see citing works
“However, Udhayakumar et al.38 reported a polyplex system using an amphipathic polypeptide for mRNA vaccine therapy.”
BackgroundIgnowski, J. M., & Schaffer, D. V. (2004) · Biotechnology and Bioengineering · doi:10.1002/bit.20059 · Cited by 164 · see citing works
Polarization of immunity induced by direct injection of naked sequence-stabilized mRNA vaccines
Carralot, J.-P., Probst, J., Hoerr, I., Scheel, B., Teufel, R., Jung, G., Rammensee, H.-G., & Pascolo, S. (2004) · Cellular and Molecular Life Sciences CMLS · doi:10.1007/s00018-004-4255-0 · Cited by 149 · see citing works
Yan, W., Chen, W., & Huang, L. (2008) · Journal of Controlled Release · doi:10.1016/j.jconrel.2008.05.005 · Cited by 125 · see citing works
Self-citationMultifunctional triblock copolymers for intracellular messenger RNA delivery
Cheng, C., Convertine, A. J., Stayton, P. S., & Bryers, J. D. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.06.020 · Cited by 123 · see citing works
Tseng, Y.-C., Xu, Z., Guley, K., Yuan, H., & Huang, L. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.02.030 · Cited by 112 · see citing works
Self-citationThe ReNAissanCe of mRNA-based cancer therapy
Van Lint, S., Renmans, D., Broos, K., Dewitte, H., Lentacker, I., Heirman, C., Breckpot, K., & Thielemans, K. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.957685 · Cited by 95 · see citing works
Zhang, Y., Peng, L., Mumper, R. J., & Huang, L. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.07.050 · Cited by 90 · see citing works
Self-citationNanoparticle Delivery of Pooled siRNA for Effective Treatment of Non-Small Cell Lung Caner
Yang, Y., Hu, Y., Wang, Y., Li, J., Liu, F., & Huang, L. (2012) · Molecular Pharmaceutics · doi:10.1021/mp300152v · Cited by 88 · see citing works
Self-citationCa2+ signaling in the regulation of dendritic cell functions
Shumilina, E. V., Huber, S. M., & Lang, F. J. W. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00039.2011 · Cited by 86 · see citing works
Koski, G. K., Schwartz, G. N., Weng, D. E., Czerniecki, B. J., Carter, C., Gress, R. E., & Cohen, P. A. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.1.82 · Cited by 85 · see citing works
Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer.
Rains, N., Cannan, R. J., Chen, W., & Stubbs, R. S. (2001) · PubMed · Cited by 79 · see citing works
Nallagatla, S. R., Toroney, R., & Bevilacqua, P. C. (2008) · RNA Biology · doi:10.4161/rna.5.3.6839 · Cited by 78 · see citing works
Exploiting dendritic cells for cancer immunotherapy: genetic modification of dendritic cells
Breckpot, K., Heirman, C., Neyns, B., & Thielemans, K. (2004) · The Journal of Gene Medicine · doi:10.1002/jgm.615 · Cited by 68 · see citing works
Bagley, K., Abdelwahab, S. F., Tuskan, R. G., et al. (2004) · Clinical and Vaccine Immunology · doi:10.1128/cdli.11.1.77-82.2004 · Cited by 55 · see citing works
PEGylation Improves Nanoparticle Formation and Transfection Efficiency of Messenger RNA
Üzgün, S., Nica, G., Pfeifer, C., Bosinco, M., Michaelis, K., Lutz, J., Schneider, M., Rosenecker, J., & Rudolph, C. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0464-z · Cited by 50 · see citing works
Xie, Y., Bai, O., Zhang, H., Li, W., & Xiang, J. (2010) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2009.0714 · Cited by 33 · see citing works
Hoerr, I. (2000) · doi:10.1002/1521-4141(200001)30:1
Flagged first, then by citations
Cited by
Sorted by citations
Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
Three decades of messenger RNA vaccine development
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2019) · Nano Today · doi:10.1016/j.nantod.2019.100766 · Cited by 342 · see citing works
Nanoplatforms for mRNA Therapeutics
Meng, C., Chen, Z., Li, G., Welte, T., & Shen, H. (2021) · Advanced Therapeutics · doi:10.1002/adtp.202000099 · Cited by 130 · see citing works
Biomedical applications of mRNA nanomedicine
Xiong, Q., Lee, G. Y., Ding, J., Li, W., & Shi, J. (2018) · Nano Research · doi:10.1007/s12274-018-2146-1 · Cited by 125 · see citing works
Melo, M., Porter, E., Zhang, Y., Silva, M., Li, N., Dobosh, B., Liguori, A., Skog, P., Landais, E., Menis, S., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.08.007 · Cited by 88 · see citing works
The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines
Wei, J., & Hui, A.-M. (2022) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2022.102405 · Cited by 57 · see citing works
Guevara, M. L., Jilesen, Z., Stojdl, D., & Persano, S. (2019) · ACS Omega · doi:10.1021/acsomega.9b00489 · Cited by 58 · see citing works
- Authors
- Wang, Y., Zhang, L., Xu, Z., Miao, L., & Huang, L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Huang, Leaf
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 26
- Issue
- 2
- Pages
- 420-434
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5835019
- OpenAlex
- W2769547311
- Cited by
- 206
- References
- 49
- Citations by year
- 2026: 13 · 2025: 27 · 2024: 37 · 2023: 31 · 2022: 38 · 2021: 26 · 2020: 17 · 2019: 10 · 2018: 7
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- NIH (CA149363, CA151652, CA149387)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- mRNA vaccines, immune checkpoint blockade, melanoma, dendritic cell targeting, mannose functionalization, antigen-presenting cells, cytotoxic T lymphocyte response, humoral immune response, tumor growth inhibition, metastasis
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Antigens, Neoplasm, Calcium Phosphates, Dendritic Cells, Disease Models, Animal, Humans, Lipids, Lymph Nodes, Melanoma, RNA, Messenger, Biomarkers, Tumor, Cancer Vaccines, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Mice, Nanoparticles, Gene Knockdown Techniques, Immunomodulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
