摘要：SummaryInterleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that tumor-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8+and CD4+T cells and M1-biased macrophages) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. Then, a neutralizing antibody against IL-34 improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy.Graphical AbstractDisplay OmittedHighlights•IL-34-expressing tumors are resistant to ICB in several murine models•IL-34 upregulates the ratio of M2-biased to M1-biased macrophage in TME•Blockade of IL-34 with neutralizing antibody (Ab) enhances the efficacy of ICB•Anti-human IL-34 Ab shows the potential to enhance PD-1 blockade efficacy in PDX modelImmunology; Cancer
