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| Item Type: | Article |
|---|---|
| Title: | Prostaglandin E(2) in a TLR3- and 7/8-agonist-based DC maturation cocktail generates mature, cytokine-producing, migratory DCs but impairs antigen cross-presentation to CD8(+) T cells |
| Creators Name: | Gierlich, P. and Lex, V. and Technau, A. and Keupp, A. and Morper, L. and Glunz, A. and Sennholz, H. and Rachor, J. and Sauer, S. and Marcu, A. and Grigoleit, G.U. and Wölfl, M. and Schlegel, P.G. and Eyrich, M. |
| Abstract: | Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E(2) (PGE(2)) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFα and IL-1ß (CDCs), focussing on the interaction of resulting DCs with CD8(+) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8(+) T-cells from naïve precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8(+) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE(2) during DC maturation and reproducible with several responder T-cell lines. In conclusion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE(2) seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides. |
| Keywords: | Dendritic Cells, Cancer Vaccines, Prostaglandin E(2), TLR Agonists, Tumor-Specific CD8(+) T Cells |
| Source: | Cancer Immunology Immunotherapy |
| ISSN: | 0340-7004 |
| Publisher: | Springer |
| Volume: | 69 |
| Number: | 6 |
| Page Range: | 1029-1042 |
| Date: | June 2020 |
| Official Publication: | https://doi.org/10.1007/s00262-019-02470-1 |
| PubMed: | View item in PubMed |
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