Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-gamma and multiple toll-like receptor agonists Journal Article

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Authors: Lovgren, T.; Sarhan, D.; Truxova, I.; Choudhary, B.; Maas, R.; Melief, J.; Nystrom, M.; Edback, U.; Vermeij, R.; Scurti, G.; Nishimura, M; Masucci, G.; Karlsson-Parra, A.; Lundqvist, A.; Adamson, L.; Kiessling, R.
Article Title: Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-gamma and multiple toll-like receptor agonists
Abstract: Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNgamma and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNgamma, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNgamma, R848, and poly I:C had the ability to activate IFNgamma production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNgamma and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.
Journal Title: Cancer immunology, immunotherapy : CII
ISSN: 1432-0851; 0340-7004
Publisher: Unknown  
Journal Place: Germany
Date Published: 2017
Language: eng
DOI/URL:

10.1007/s00262-017-2029-4
Notes: LR: 20170611; JID: 8605732; OTO: NOTNLM; 2016/12/13 [received]; 2017/06/05 [accepted]; aheadofprint