Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.
J Exp Med. 2013 Aug 26;210(9):1711-28. doi: 10.1084/jem.20130440. Epub 2013 Jul 29.
Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol-CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol-CXCR2 axis and a possible target for cancer therapy.
肿瘤浸润免疫细胞可以被微环境中释放的分子调节，从而破坏抗肿瘤免疫反应，促进肿瘤生长。在免疫细胞中，中性粒细胞通过促进新生血管生成和/或抑制抗肿瘤免疫反应而发挥重要的促肿瘤作用。最近的研究表明，肿瘤衍生的氧化固醇通过抑制树突状细胞向淋巴器官的迁移，有利于肿瘤生长。我们报告称，肿瘤衍生的氧化固醇以肝 X 受体（LXR）非依赖、CXCR2 依赖的方式募集促肿瘤中性粒细胞，从而通过促进新生血管生成和免疫抑制促进肿瘤生长。我们证明，干扰氧化固醇-CXCR2 轴可延迟肿瘤生长并延长荷瘤小鼠的总生存期。这些结果确定了氧化固醇-CXCR2 轴的一个意外的促肿瘤功能，以及癌症治疗的一个可能靶点。
