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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2943-2955
Number of pages13
JournalCancer Immunology, Immunotherapy
Volume71
Issue number12
DOIs
StatePublished - Dec 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Keywords

  • CD1d
  • GM-CSF
  • Invariant NKT cell
  • Prostate cancer
  • Tumor vaccine
  • α-Galactosylceramide

Fingerprint

Dive into the research topics of 'Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model'. Together they form a unique fingerprint.

Cite this