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Abstract
Background In recent years, immunotherapy has become a common tool of cancer treatment. In order to define therapeutic targets, it is necessary to understand mechanisms of tumor-induced immunosuppression. In malignant B-cell lymphoma, the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) remain poorly understood.
Methods To investigate the role of IL-10 in a tumor microenvironment, we used λ-MYC-transgenic mice that spontaneously develop B-cell lymphoma. The experiments were performed either in vivo or in vitro and the cell samples were then analyzed by flow cytometry.
Results In MYC tumors, CD4+Foxp3- effector T cells maintained the expression of interferon-γ (IFN-γ), yet became exhausted. Within this population we found a cell fraction of unknown origin coexpressing IFN-γ and IL-10 that increased during disease progression. These cells turned out to be T regulatory type 1 (Tr1) cells, which are known to be immunosuppressive. When exposing homogeneous IFN-γ-producing T helper type 1 (Th1) cells to a MYC tumor milieu in vitro, part of these cells started to express both, IFN-γ and IL-10, and showed an increased level of programmed cell death protein 1 (PD-1). Notably, these changes diminished when an IL-10 neutralizing monoclonal antibody (mAb) was added to the coculture, indicating that IL-10 is necessary for the Tr1 development and is involved in the upregulation of PD-1. In line with these results, we treated λ-MYC mice with anti-IL-10 mAb. This therapy not only led to significantly prolonged survival but also decreased expression of PD-1 on effector T cells and increased proliferation of cytotoxic T cells.
Conclusions In summary, these results showed the importance of IL-10 for the tumor immune escape in lymphoma. IL-10 induced a conversion from Th1 to Tr1 cells and elevated levels of PD-1. Both effects were diminished after IL-10 ablation. Thus, targeting IL-10 might be a promising new approach of immunotherapy.
Ethics Approval All animal studies were approved by Regierung von Oberbayern, approval number 55.2-1-54.
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