Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
Inserm U1223, Institut Pasteur, Paris, France.
Nat Immunol. 2019 Mar;20(3):257-264. doi: 10.1038/s41590-019-0321-5. Epub 2019 Feb 18.
Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited.
二肽基肽酶 4（DPP4，也称为 CD26）介导的趋化因子翻译后修饰已被证明可负向调节淋巴细胞迁移，其抑制作用可通过保留功能性趋化因子 CXCL10 来增强 T 细胞迁移和肿瘤免疫。通过将这些最初的发现扩展到肝细胞癌和乳腺癌的临床前模型，我们发现了 DPP4 抑制作用改善抗肿瘤反应的一种独特机制。施用二肽基肽酶 4 抑制剂西他列汀会导致趋化因子 CCL11 的浓度升高，并增加嗜酸性粒细胞向实体瘤的迁移。在缺乏淋巴细胞的小鼠中，增强的肿瘤控制得以保留，而在嗜酸性粒细胞耗竭或用脱颗粒抑制剂治疗后则被消除。我们进一步证明，肿瘤细胞表达警报素 IL-33 对于嗜酸性粒细胞介导的抗肿瘤反应是必需且充分的，并且该机制有助于检查点抑制剂治疗的疗效。这些发现深入了解了 IL-33 和嗜酸性粒细胞介导的肿瘤控制，当内源性 DPP4 免疫调节机制被抑制时，这种机制就会显现出来。
