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Open Access 01-10-2017 | Original Article

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

Authors: Tanja Lövgren, Dhifaf Sarhan, Iva Truxová, Bhavesh Choudhary, Roeltje Maas, Jeroen Melief, Maria Nyström, Ulrika Edbäck, Renee Vermeij, Gina Scurti, Michael Nishimura, Giuseppe Masucci, Alex Karlsson-Parra, Andreas Lundqvist, Lars Adamson, Rolf Kiessling

Published in: Cancer Immunology, Immunotherapy | Issue 10/2017

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 IFNγ 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 IFNγ, 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 IFNγ, R848, and poly I:C had the ability to activate IFNγ 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 IFNγ 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.

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Title: Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists
Authors: Tanja Lövgren
Dhifaf Sarhan
Iva Truxová
Bhavesh Choudhary
Roeltje Maas
Jeroen Melief
Maria Nyström
Ulrika Edbäck
Renee Vermeij
Gina Scurti
Michael Nishimura
Giuseppe Masucci
Alex Karlsson-Parra
Andreas Lundqvist
Lars Adamson
Rolf Kiessling
Publication date: 01-10-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 10/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2029-4

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