Inserm UMR1037, Cancer Research Center of Toulouse, 31037, Toulouse, France.
Equipe Labellisée Ligue Contre Le Cancer, 31037, Toulouse, France.
Nat Commun. 2020 Jan 23;11(1):437. doi: 10.1038/s41467-019-14218-7.
Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
免疫检查点抑制剂（ICIs）显著改变了几种晚期癌症的预后，但许多患者对治疗仍无反应。通过靶向癌细胞代谢来调节免疫抑制性肿瘤微环境，可能会获得最佳效果。在这里，我们发现鞘氨醇激酶-1（SK1）是抗肿瘤免疫的关键调节因子。在接受抗 PD-1 治疗的转移性黑色素瘤患者中，肿瘤细胞中 SK1 表达增加与生存期更短显著相关。在黑色素瘤、乳腺癌和结肠癌的小鼠模型中，靶向 SK1 可显著增强对 ICI 的反应。从机制上讲，SK1 沉默可降低肿瘤微环境中各种免疫抑制因子的表达，从而限制调节性 T 细胞（Treg）浸润。因此，在人类黑色素瘤活检中也观察到 SK1 依赖性免疫抑制特征。总之，这项研究确定 SK1 为一种检查点脂质激酶，可作为增强免疫治疗的靶点。
