The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2021-05, Vol.70 (5), p.1343-1350
• Main Authors: Scheuerpflug, Anne, Ahmetlić, Fatima, Bauer, Vera, Riedel, Tanja, Röcken, Martin, Mocikat, Ralph
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antitumor activity; B-cell lymphoma; Cancer Research; Cells, Cultured; Costimulator; CTLA-4 Antigen - immunology; CTLA-4 protein; Dendritic cells; Dendritic Cells - immunology; Disease Models, Animal; Drug Therapy, Combination; Genes, myc - genetics; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - therapeutic use; Immunology; Interleukin 10; Interleukin 12; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - surgery; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Myc protein; Natural killer cells; Oncology; Original; Original Article; PD-1 protein; Programmed Cell Death 1 Receptor - immunology; Transgenic mice; γ-Interferon
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02767-6

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-MYC-transgenic 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.