[Stimulatory and inhibitory signaling pathways of the T cell-APC interaction and the effect of TLR agonists on APCs].

Autor: Kürten CHL; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland., Deuß E; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland., Lei YL; Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA., Höing B; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland., Kramer B; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Mannheim, Universität Heidelberg, Mannheim, Deutschland., Lang S; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland., Ferris RL; Cancer Immunology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA., Kansy BA; Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland. benjamin.kansy@uk-essen.de.
Jazyk: němčina
Zdroj: HNO [HNO] 2020 Dec; Vol. 68 (12), pp. 916-921. Date of Electronic Publication: 2020 Oct 30.
DOI: 10.1007/s00106-020-00960-8
Abstrakt: Background: CD8 + cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8 + T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs).
Objective: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction.
Materials and Methods: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48 h of CD14 + cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8 + T cells were stimulated for 72 h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD‑1, Tim‑3, CTLA4, and Lag3 by flow cytometry.
Results: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD‑1 checkpoint blockade.
Conclusion: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8 + T cell exhaustion. The effect of PD‑1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.
Databáze: MEDLINE
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