Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability
Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery...
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| Format: | Article |
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American Association for Cancer Research
2018
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| Online Access: | http://hdl.handle.net/1721.1/117745 https://orcid.org/0000-0001-5286-4060 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0003-2599-2774 |
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| author | Karver, Mark R. Dinter, Jens Gall, Sylvie Le Moynihan, Kelly Dare Holden, Rebecca Lynn Mehta, Naveen Wang, Chensu Liang, Simon Abraham, Wuhbet Melo, Mariane Bandeira Zhang, Angela Q. Li, Na Pentelute, Bradley L. Irvine, Darrell J |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Karver, Mark R. Dinter, Jens Gall, Sylvie Le Moynihan, Kelly Dare Holden, Rebecca Lynn Mehta, Naveen Wang, Chensu Liang, Simon Abraham, Wuhbet Melo, Mariane Bandeira Zhang, Angela Q. Li, Na Pentelute, Bradley L. Irvine, Darrell J |
| author_sort | Karver, Mark R. |
| collection | MIT |
| description | Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week in vivo, whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required Batf3-dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines. |
| first_indexed | 2024-09-23T13:52:43Z |
| format | Article |
| id | mit-1721.1/117745 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:52:43Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/1177452022-10-01T17:41:52Z Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability Karver, Mark R. Dinter, Jens Gall, Sylvie Le Moynihan, Kelly Dare Holden, Rebecca Lynn Mehta, Naveen Wang, Chensu Liang, Simon Abraham, Wuhbet Melo, Mariane Bandeira Zhang, Angela Q. Li, Na Pentelute, Bradley L. Irvine, Darrell J Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT Moynihan, Kelly Dare Holden, Rebecca Lynn Mehta, Naveen Wang, Chensu Liang, Simon Abraham, Wuhbet Melo, Mariane Bandeira Zhang, Angela Q. Li, Na Pentelute, Bradley L. Irvine, Darrell J Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week in vivo, whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required Batf3-dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines. National Cancer Institute (U.S.) (Grant P30-CA14051) 2018-09-13T18:20:51Z 2018-09-13T18:20:51Z 2018-06 2018-04 2018-09-06T17:54:50Z Article http://purl.org/eprint/type/JournalArticle 2326-6066 2326-6074 http://hdl.handle.net/1721.1/117745 Moynihan, Kelly D. et al. “Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability.” Cancer Immunology Research 6, 9 (June 2018): 1025–1038 © 2018 AACR https://orcid.org/0000-0001-5286-4060 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0003-2599-2774 http://dx.doi.org/10.1158/2326-6066.CIR-17-0607 Cancer Immunology Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research Other repository |
| spellingShingle | Karver, Mark R. Dinter, Jens Gall, Sylvie Le Moynihan, Kelly Dare Holden, Rebecca Lynn Mehta, Naveen Wang, Chensu Liang, Simon Abraham, Wuhbet Melo, Mariane Bandeira Zhang, Angela Q. Li, Na Pentelute, Bradley L. Irvine, Darrell J Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title | Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title_full | Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title_fullStr | Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title_full_unstemmed | Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title_short | Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability |
| title_sort | enhancement of peptide vaccine immunogenicity by increasing lymphatic drainage and boosting serum stability |
| url | http://hdl.handle.net/1721.1/117745 https://orcid.org/0000-0001-5286-4060 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0003-2599-2774 |
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