Interleukin-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.

Interleukin-34 (IL-34) 是 CSF-1 受体的集落刺激因子 1 (CSF-1) 的替代配体，作为单核细胞/巨噬细胞谱系的关键调节因子。在这项研究中，我们表明，无论各种小鼠癌症模型中是否存在 CSF-1，肿瘤源性 IL-34 都会介导对免疫检查点阻断的抵抗。与其免疫抑制特性一致，肿瘤中 IL-34 的表达与肿瘤微环境中细胞（例如 CD8 ⁺和 CD4 ⁺ T 细胞以及 M1 偏向巨噬细胞）和分子（包括各种细胞因子和趋化因子）效应子频率的降低相关。然后，针对 IL-34 的中和抗体改善了组合治疗模型（包括患者来源的异种移植模型）中免疫检查点阻断的治疗效果。总的来说，我们发现肿瘤源性 IL-34 会抑制免疫检查点阻断的功效，并提出将 IL-34 阻断作为癌症治疗的新策略。