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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-gamma and multiple toll-like receptor agonists
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Karolinska Institute; Karolinska University Hospital.
Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden.;Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA..
Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
Karolinska Inst, Dept Oncol Pathol, Canc Ctr Karolinska, Stockholm, Sweden..
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2017 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 66, no 10, p. 1333-1344Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
SPRINGER , 2017. Vol. 66, no 10, p. 1333-1344
Keyword [en]
Cancer, Dendritic cell-vaccine, IFN gamma, R848, Poly I:C, LPS
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-337075DOI: 10.1007/s00262-017-2029-4ISI: 000412228500008OAI: oai:DiVA.org:uu-337075DiVA: diva2:1179732
Funder
Swedish Cancer Society, 2013/379Knut and Alice Wallenberg FoundationNIH (National Institute of Health), NIH P01 CA154778NIH (National Institute of Health), NIH R01 CA10494
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-02Bibliographically approved

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