The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors
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ORIGINAL ARTICLE
The role of dendritic cells for therapy of B‑cell lymphoma with immune checkpoint inhibitors Anne Scheuerpflug1 · Fatima Ahmetlić1,2 · Vera Bauer1 · Tanja Riedel2 · Martin Röcken3 · Ralph Mocikat1,2 Received: 8 June 2020 / Accepted: 15 October 2020 © The Author(s) 2020
Abstract Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYCtransgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses. Keywords Immune checkpoint blocking · Lymphoma · Tumor-infiltrating dendritic cells · Interferon-γ · λ-MYC mouse
Introduction In the past years, immune checkpoint blockade (ICB) has substantially advanced the field of cancer immunotherapy in the clinics. Approaches have been conceived to block counter-regulatory molecules like cytotoxic T-lymphocyteassociated protein-4 (CTLA-4) or programmed death-1 (PD-1), which are often associated with tumor-infiltrating T cells (TILs) whose functions are silenced or exhausted in the tumor microenvironment [1–6]. Although monoclonal Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02767-6) contains supplementary material, which is available to authorized users. * Ralph Mocikat Mocikat@helmholtz‑muenchen.de 1
Helmholtz-Zentrum München, Eigenständige Forschungseinheit Translationale Molekulare Immunologie, Munich, Germany
2
Helmholtz-Zentrum München, Institut Für Molekulare Immunologie, Munich, Germany
3
Klinik Für Dermatologie, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
antibodies (mAbs) targeting CTLA-4 or PD-1, such as Ipilimumab or Nivolumab and Pembrolizumab, have already been successfully established as new tools for treating several types of cancer including lymphoma (reviews in [7–10]), the underlying tumor-suppressive mechanisms are not yet completely understood. While the rationale of ICB originally aimed at re-activatin
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