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-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.
Highlights
In the past years, immune checkpoint blockade (ICB) has substantially advanced the field of cancer immunotherapy in the clinics
Λ-MYC mice, which are of C57BL/6 origin, constitutively express a transgenic c-MYC oncogene in a B-cell-specific manner, which leads to the development of endogenous B-cell lymphomas in 100% of mice [11]
In the λ-MYC lymphoma model, we showed that IFN-γ is strictly required for successful therapy [12, 13]
Summary
Immune checkpoint blockade (ICB) has substantially advanced the field of cancer immunotherapy in the clinics. While the rationale of ICB originally aimed at re-activating TILs against malignant cells by directly disrupting the interaction between the counter-regulatory receptors on T cells and their ligands, other pathways and cell populations are involved in mediating the therapeutic effect. Interferon-γ (IFN-γ) and tumor necrosis factor (TNF) were strictly required for tumor control in this model [13]. These cytokines are capable of activating the p16Ink4a-Rb and the p53-p21 signaling pathways [13, 14], thereby causing cell cycle arrest of cancer cells [14, 15]. The effect of ICB was mediated by cytokine-induced senescence of malignant cells [12, 13]. IFN-γ, which was required for this pathway, was provided by T cells upon ICB, and by NK cells,
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