Gamma-butyrobetaine hydroxylase 1 confers metastatic advantage by shielding cancer cells from natural killer cell immunosurveillance

Primary tumors constantly shed cancer cells into the circulation, yet only a fraction of these cells manage to give rise to metastatic tumors. Success appears to depend on metabolic changes within metastatic tumor cells, but few details are known. Here we report that expression of the enzyme γ-butyrobetaine hydroxylase 1 (BBOX1) under the control of a super enhancer allows a subset of cells in various types of tumors to produce the metabolite cartinine, which inhibits the small GTPase RhoA in natural killer cells, preventing immunological synapse formation and thereby protecting the metastatic cells from destruction. Knocking down γ-butyrobetaine hydroxylase 1 in tumor cells promoted their destruction by natural killer cells in vitro and improved the efficacy of natural killer cell adoptive transfer therapy in vivo. These findings illustrate how a subpopulation of tumor cells hijacks the metabolite carnitine to evade immune surveillance in the tumor microenvironment. Targeting γ-butyrobetaine hydroxylase 1 may be a powerful anti-metastatic strategy.实体瘤会持续向血液循环系统中释放癌细胞，但其中仅有极小部分能够形成转移性肿瘤。该定植过程的成功与否似乎取决于转移性肿瘤细胞内的代谢重塑，但目前相关分子细节仍有待阐明。本研究报道，在超级增强子（super enhancer）的调控下，酶γ-丁基甜菜碱羟化酶1（γ-butyrobetaine hydroxylase 1，BBOX1）的表达可使多种肿瘤中的细胞亚群产生代谢物肉碱（carnitine，原文写为cartinine，疑似拼写笔误），该代谢物可抑制自然杀伤细胞（natural killer cells）内的小GTP酶RhoA（small GTPase RhoA），阻碍免疫突触（immunological synapse）的形成，进而使转移性肿瘤细胞免于被清除。在肿瘤细胞中敲低γ-丁基甜菜碱羟化酶1的表达，可在体外促进自然杀伤细胞对肿瘤细胞的杀伤清除，并在体内提升自然杀伤细胞过继转移疗法的治疗效果。上述研究结果揭示了肿瘤细胞亚群如何通过劫持代谢物肉碱，在肿瘤微环境（tumor microenvironment）中逃避免疫监视。靶向γ-丁基甜菜碱羟化酶1或可成为一种高效的抗转移治疗策略。