TY  - JOUR
A1  - Gierlich, Philipp
A1  - Lex, Veronika
A1  - Technau, Antje
A1  - Keupp, Anne
A1  - Morper, Lorenz
A1  - Glunz, Amelie
A1  - Sennholz, Hanno
A1  - Rachor, Johannes
A1  - Sauer, Sascha
A1  - Marcu, Ana
A1  - Grigoleit, Götz Ulrich
A1  - Wölfl, Matthias
A1  - Schlegel, Paul G.
A1  - Eyrich, Matthias
T1  - 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
JF  - Cancer Immunology, Immunotherapy
N2  - 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  PGE2 during DC maturation and reproducible with several responder T-cell lines. In conclu-sion, 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.
KW  - dendritic cells
KW  - cancer vaccines
KW  - prostaglandin  E2
KW  - TLR agonists
KW  - tumor-specific  CD8+ T cells
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232311
SN  - 0340-7004
VL  - 69
ER  -