An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells
An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells
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DOI：
10.1016/j.immuni.2020.06.016
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发表时间：
2020-07-14
期刊：
影响因子：
32.4
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
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作者：
Kumagai, Shogo;Togashi, Yosuke;Nishikawa, Hiroyoshi
只有一小部分胃癌（GC）患者对免疫检查点阻断（ICB）有反应。为了研究这种抵抗的机制，我们检查了GC的免疫景观。这些肿瘤的一个子集的特征在于高频率的调节性T（Treg）细胞和低数量的效应T细胞。基因组分析显示，这些肿瘤在RHOA中具有已知会驱动肿瘤进展的突变。癌细胞中的RHOA突变激活了PI 3 K-AKT-mTOR信号通路，增加了游离脂肪酸的产生，Treg细胞比效应T细胞更有效地消耗这些游离脂肪酸。RHOA突变肿瘤对PD-1阻断具有抗性，但对PD-1阻断与PI 3 K通路抑制剂或靶向Treg细胞的疗法的组合有反应。我们提出，RHOA突变所赋予的代谢优势使Treg细胞在GC肿瘤内积累，产生免疫抑制性TME，这是对ICB耐药的基础。
Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.