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- Title
Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.
- Authors
Varghese, Bindu; Lynch, Lydia; Vriend, Lianne E.; Draganov, Dobrin; Clark, Justice M.; Kissick, Haydn T.; Varghese, Sharlin; Sanda, Martin G.; Dranoff, Glenn; Arredouani, M. Simo; Balk, Steven P.; Exley, Mark A.
- Abstract
Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation.
- Subjects
PROSTATE cancer; CANCER vaccines; VACCINE effectiveness; CYTOTOXIC T cells; MILKFAT; EPIDERMAL growth factor
- Publication
Cancer Immunology, Immunotherapy, 2022, Vol 71, Issue 12, p2943
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-022-03210-8