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Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ

Stimulatory and inhibitory signaling pathways of the T cell–APC interaction and the effect of TLR agonists on APCs

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Zusammenfassung

Hintergrund

CD8+-T-Effektor-Zellen spielen eine Schlüsselrolle in der Identifikation und Elimination von Tumorzellen. Tumoren entkommen einer effektiven T‑Zell-Antwort durch Induktion eines Erschöpfungszustands, der die zytotoxische Kapazität der Effektorzellen mindert. Neuartige Checkpointinhibitoren wirken u. a. durch Reaktivierung erschöpfter, dysfunktionaler T‑Zellen. CD8+-T-Zellen eliminieren Tumorzellen nach Darbietung tumorspezifischer Antigene durch antigenpräsentierende Zellen (APZ). Die APZ-vermittelte Tumorerkennung wird v. a. Toll-like-Rezeptoren (TLR) stimuliert.

Ziel der Arbeit

Untersucht wurde der Einfluss von TLR-Agonisten auf APZ sowie stimulierende und inhibierende Signalwege der T‑Zell- und APZ-Interaktion.

Material und Methoden

Die Genexpression von Interleukin (IL-)12 und PDL1 wurde nach Stimulation von CD14+-Zellen mit CpG über 0, 8, 24 und 48 h analysiert. Die Expression des inhibitorischen kappa-B-Proteins (IκBα) nach Stimulation mit CpG wurde mittels Westernblot ausgewertet. CD8+-T-Zellen wurden über 72 h mit und ohne PD1-Checkpointblockade stimuliert und mittels Durchflusszytometrie auf die Expression von PD1, Tim‑3, CTLA4 und Lag3 untersucht.

Ergebnisse

Durch TLR-Stimulation (unmethylierte CpG-DNA) von APZ wurden immunstimulierende Signale wie die IL-12-Expression gesteigert, aber auch immuninhibierende Signalwege wie die PDL1-Expression aktiviert. Diese Signalwege werden NF-κB-vermittelt. Nach alleiniger Blockade der PD1-PDL1-Signalwege zeigte sich eine Überexpression anderer Immuncheckpointrezeptoren als potenzielle Ursache für fehlendes Ansprechen auf TLR-Stimulation mit PD1-Checkpointblockade.

Schlussfolgerung

Durch eine TLR-Stimulation exprimieren APZ im Tumormikromilieu NF-κB-vermittelt PDL1 und tragen so zur Erschöpfung von CD8+-T-Zellen bei. Der Effekt einer PD1-Blockade wird dabei potenziell durch Überexpression anderer Checkpointinhibitoren beeinträchtigt.

Abstract

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.

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Authors and Affiliations

  1. Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland

    C. H. L. Kürten, E. Deuß, B. Höing, S. Lang &  B. A. Kansy

  2. 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

    Y. L. Lei

  3. Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie, Universitätsklinikum Mannheim, Universität Heidelberg, Mannheim, Deutschland

    B. Kramer

  4. Cancer Immunology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    R. L. Ferris

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  1. C. H. L. Kürten
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  2. E. Deuß
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  6. S. Lang
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Correspondence to B. A. Kansy.

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Interessenkonflikt

C.H.L. Kürten, E. Deuß, Y. L. Lei, B. Höing, B. Kramer, S. Lang,R. L. Ferris und B. A. Kansy geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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C. H. L. Kürten und E. Deuß teilen sich die Erstautorenschaft.

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Kürten, C.H.L., Deuß, E., Lei, Y.L. et al. Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ . HNO 68, 916–921 (2020). https://doi.org/10.1007/s00106-020-00960-8

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