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

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1333-1344
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume66
Issue number10
DOIs
StatePublished - Oct 1 2017

Bibliographical note

Funding Information:
Conflict of interest R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest.

Funding Information:
Acknowledgements This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V’s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. Lövgren), Stiftelsen Längmanska kulturfonden (T. Lövgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol.

Funding Information:
This work was supported by The Swedish Cancer Society (R. Kiessling; 2013/379), The Cancer Society in Stockholm and The King Gustaf V?s Jubilee Foundation (R. Kiessling; 144102), The Swedish Medical Research Council (R. Kiessling; 521-2013-4100), Stockholm City Council Project Grant (R. Kiessling; ALF Medicin 2015, 20140036), Knut and Alice Wallenberg Foundations (R. Kiessling), O.E och Edla Johanssons vetenskapliga stiftelse (T. L?vgren), Stiftelsen L?ngmanska kulturfonden (T. L?vgren), and the National Institutes of Health (M. Nishimura; NIH P01 CA154778 and NIH R01 CA10494). We thank A.M. Salazar (Oncovir, Inc.) for providing Hiltonol. In part previously published in ?Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival,? September 16?19, 2015, New York, NY, USA. Title: ?Enhanced IL-12 production and T cell stimulation ability by dendritic cells matured in presence of GMP-grade Toll-like receptor ligands and IFN-?,? Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B071. R Kiessling is in the Scientific Advisory Board for the companies Immunicum AB, Idogen Inc, Glactone Pharma AB, and Clinical Laserthermia Systems AB, and has received compensation for arranging courses for Bristol Myers Squibb and a research grant from Moderna Therapeutics. A. Karlsson-Parra is employed by, and a shareholder of, Immunicum AB. All other authors declare that they have no conflicts of interest.

Publisher Copyright:
© 2017, The Author(s).

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • Cancer
  • Dendritic cell-vaccine
  • IFNγ
  • LPS
  • Poly I:C
  • R848

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