期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 66, 期 10, 页码 1333-1344出版社
SPRINGER
DOI: 10.1007/s00262-017-2029-4
关键词
Cancer; Dendritic cell-vaccine; IFN gamma; R848; Poly I:C; LPS
资金
- Swedish Cancer Society [2013/379]
- Cancer Society in Stockholm
- King Gustaf V's Jubilee Foundation [144102]
- Swedish Medical Research Council [521-2013-4100]
- Stockholm City Council Project [20140036]
- Knut and Alice Wallenberg Foundations
- O.E och Edla Johanssons vetenskapliga stiftelse
- Stiftelsen Langmanska kulturfonden
- National Institutes of Health [NIH P01 CA154778, NIH R01 CA10494]
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.
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