Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells
| dc.contributor.author | Ostrand-Rosenberg, Suzanne | |
| dc.contributor.author | Horn, Lucas A. | |
| dc.contributor.author | Alvarez, Juan A. | |
| dc.date.accessioned | 2019-03-05T18:35:59Z | |
| dc.date.available | 2019-03-05T18:35:59Z | |
| dc.date.issued | 2015-03-20 | |
| dc.description.abstract | We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4⁺T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented tumor cell-expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1⁺ activated T cells in the presence of PD-L1⁺ human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells. | en_US |
| dc.description.sponsorship | This work was supported by grants from the U.S. National Institutes of Health (RO1CA84232) and the State of Maryland Technology Development Corp. (TEDCO; 1000308). | en_US |
| dc.description.uri | https://link.springer.com/article/10.1007%2Fs00262-015-1677-5 | en_US |
| dc.format.extent | 13 pages | en_US |
| dc.genre | journal articles postprints | en_US |
| dc.identifier | doi:10.13016/m2uryn-7djh | |
| dc.identifier.citation | Suzanne Ostrand-Rosenberg, Lucas A. Horn, and Juan A. Alvarez, Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells, Cancer Immunology, Immunotherapy, October 2015, Volume 64, Issue 10, pp 1287–1293 , https://dx.doi.org/10.1007%2Fs00262-015-1677-5 | en_US |
| dc.identifier.uri | https://dx.doi.org/10.1007%2Fs00262-015-1677-5 | |
| dc.identifier.uri | http://hdl.handle.net/11603/12931 | |
| dc.language.iso | en_US | en_US |
| dc.publisher | Springer Nature Switzerland AG. | en_US |
| dc.relation.isAvailableAt | The University of Maryland, Baltimore County (UMBC) | |
| dc.relation.ispartof | UMBC Biological Sciences Department Collection | |
| dc.relation.ispartof | UMBC Faculty Collection | |
| dc.rights | This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author. | |
| dc.rights | This is a post-peer-review, pre-copyedit version of an article published in Cancer Immunology, Immunotherapy. The final authenticated version is available online at: https://dx.doi.org/10.1007%2Fs00262-015-1677-5 | |
| dc.subject | Tumor-induced immune suppression | en_US |
| dc.subject | T cell activation | en_US |
| dc.subject | checkpoint blockade molecules | en_US |
| dc.subject | PD-1 pathway | en_US |
| dc.subject | cancer immunotherapy | en_US |
| dc.subject | PIVAC 14 | en_US |
| dc.title | Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells | en_US |
| dc.type | Text | en_US |