Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles
Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here,...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2015
|
| Online Access: | http://hdl.handle.net/1721.1/99425 https://orcid.org/0000-0002-5687-6154 |
| _version_ | 1811087516505210880 |
|---|---|
| author | Stephan, Matthias T. Stephan, Sirkka B. Bak, Peter Chen, Jianzhu Irvine, Darrell J |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Stephan, Matthias T. Stephan, Sirkka B. Bak, Peter Chen, Jianzhu Irvine, Darrell J |
| author_sort | Stephan, Matthias T. |
| collection | MIT |
| description | Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface. |
| first_indexed | 2024-09-23T13:47:20Z |
| format | Article |
| id | mit-1721.1/99425 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:47:20Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/994252022-09-28T16:10:54Z Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles Stephan, Matthias T. Stephan, Sirkka B. Bak, Peter Chen, Jianzhu Irvine, Darrell J Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Materials Science and Engineering Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Stephan, Matthias T. Stephan, Sirkka B. Bak, Peter Chen, Jianzhu Irvine, Darrell J. Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface. National Institutes of Health (U.S.) (CA140476) National Institutes of Health (U.S.) (EB123622) United States. Dept. of Defense. Prostate Cancer Research Program (W81XWH-10-1-0290) National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051) National Cancer Institute (U.S.) American Cancer Society (Postdoctoral Fellowship 12109-PF-11-025-01-LIB) 2015-10-23T13:42:54Z 2015-10-23T13:42:54Z 2012-05 2012-03 Article http://purl.org/eprint/type/JournalArticle 01429612 1878-5905 http://hdl.handle.net/1721.1/99425 Stephan, Matthias T., Sirkka B. Stephan, Peter Bak, Jianzhu Chen, and Darrell J. Irvine. “Synapse-Directed Delivery of Immunomodulators Using T-Cell-Conjugated Nanoparticles.” Biomaterials 33, no. 23 (August 2012): 5776–5787. https://orcid.org/0000-0002-5687-6154 en_US http://dx.doi.org/10.1016/j.biomaterials.2012.04.029 Biomaterials Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Stephan, Matthias T. Stephan, Sirkka B. Bak, Peter Chen, Jianzhu Irvine, Darrell J Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title | Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title_full | Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title_fullStr | Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title_full_unstemmed | Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title_short | Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles |
| title_sort | synapse directed delivery of immunomodulators using t cell conjugated nanoparticles |
| url | http://hdl.handle.net/1721.1/99425 https://orcid.org/0000-0002-5687-6154 |
| work_keys_str_mv | AT stephanmatthiast synapsedirecteddeliveryofimmunomodulatorsusingtcellconjugatednanoparticles AT stephansirkkab synapsedirecteddeliveryofimmunomodulatorsusingtcellconjugatednanoparticles AT bakpeter synapsedirecteddeliveryofimmunomodulatorsusingtcellconjugatednanoparticles AT chenjianzhu synapsedirecteddeliveryofimmunomodulatorsusingtcellconjugatednanoparticles AT irvinedarrellj synapsedirecteddeliveryofimmunomodulatorsusingtcellconjugatednanoparticles |