Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells
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Date
2015-03-20
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Citation of Original Publication
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
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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
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
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.