Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.

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.

• Authors: Bindu Varghese, Lydia Lynch, Lianne E Vriend, Dobrin Draganov, Justice M Clark, Haydn T Kissick, Sharlin Varghese, Martin G Sanda, Glenn Dranoff, M Simo Arredouani, Steven P Balk, Mark A Exley
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 71 Issue 12 Pg. 2943-2955 (Dec 2022) ISSN: 1432-0851 [Electronic] Germany
• PMID: 35523889 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Cancer Vaccines
• Granulocyte-Macrophage Colony-Stimulating Factor
• Galactosylceramides
• Interleukin-12
• Vaccines, Combined
• Antigens, Viral, Tumor
• EGF Family of Proteins
• Oligopeptides

Topics

• Male
• Mice
• Animals
• Humans
• Natural Killer T-Cells
• Cancer Vaccines
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Lymphocyte Activation
• Galactosylceramides
• Interleukin-12 (pharmacology)
• Prostatic Neoplasms (therapy, metabolism)
• Vaccines, Combined (pharmacology)
• Antigens, Viral, Tumor
• EGF Family of Proteins (metabolism, pharmacology)
• Oligopeptides (pharmacology)
• Mice, Inbred C57BL