日本国立癌症中心研究所/肿瘤探索研究与临床试验中心（EPOC）Hiroyoshi Nishikawa和Yosuke Togashi研究组取得最新进展。他们发现致癌性改变通过赋予调节性T（Treg）细胞代谢优势，创造了促进肿瘤进展的微环境。这一研究成果发表在2020年7月7日出版的《免疫》上。

为了研究耐药性的潜在机制，研究人员检查了胃癌（GC）的免疫情况。这些肿瘤的一个亚群以高频率的Treg细胞和少量的效应T细胞为特征。基因组分析表明，这些肿瘤的RHOA突变，已知具有驱动肿瘤进展的作用。癌细胞中的RHOA突变激活了PI3K-AKT-mTOR信号传导途径，增加了游离脂肪酸的产生，与效应T细胞相比，Treg细胞更有效地消耗了游离脂肪酸。

RHOA突变型肿瘤对PD-1封闭有抵抗力，但对PD-1封闭与PI3K途径抑制剂或靶向Treg细胞的疗法的联合治疗有反应。研究人员认为，由RHOA突变赋予的代谢优势使Treg细胞在GC肿瘤内积累，从而产生对免疫检查点封锁（ICB）产生抗性的免疫抑制性肿瘤微环境。

附：英文原文

Title: An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells

Author: Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa

Issue&Volume: 2020-07-07

Abstract: Only a small percentage of patients afflicted with gastric cancer (GC) respond toimmune checkpoint blockade (ICB). To study the mechanisms underlying this resistance,we examined the immune landscape of GC. A subset of these tumors was characterizedby 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, increasingproduction of free fatty acids that are more effectively consumed by Treg cells thaneffector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. Wepropose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressiveTME that underlies resistance to ICB.

DOI: 10.1016/j.immuni.2020.06.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30271-5