Fatty acid metabolism constrains Th9 cell differentiation and antitumor immunity via the modulation of retinoic acid receptor signaling  

作　　者：Takahiro Nakajima Toshio Kanno Yuki Ueda Keisuke Miyako Takeru Endo Souta Yoshida Satoru Yokoyama Hikari KAsou Kazuko Yamada Kazutaka Ikeda Yosuke Togashi Yusuke Endo 

机构地区：[1]Department of Frontier Research and Development,Laboratory of Medical Omics Research,Kazusa DNA Research Institute,2-6-7 Kazusa Kamatari,Kisarazu,Chiba 292-0818,Japan [2]Department of Tumor Microenvironment,Faculty of Medicine,Dentistry and Pharmaceutical Sciences,Okayama University,2-5-1,Shikata-cho,Kita-ku,Okayama 7008558,Japan [3]Department of Applied Genomics,Kazusa DNA Research Institute,2-6-7 Kazusa Kamatari,Kisarazu,Chiba 292-0818,Japan [4]Division of Cell Therapy,Chiba Cancer Center Research Institute,666-2 Nitona-cho,Chuo-ku,Chiba 260-8717,Japan [5]Department of Omics Medicine,Graduate School of Medicine,Chiba University,1-8-1 Inohana,Chuo-ku,Chiba 260-8670,Japan

出　　处：《Cellular & Molecular Immunology》2024年第11期1266-1281,共16页中国免疫学杂志(英文版)

基　　金：supervised by Osamu Ohara at the Department of Applied Genomics,Kazusa DNA Research Institute and was supported by grants from the Ministry of Education,Culture,Sports,Science and Technology of Japan(Grants-in-Aid:Grant-in-Aid for Scientific Research[B]#20H03455;Challenging Research(Exploratory)#20K21618;Early-Career Scientists#21K15476 and#22K15502;and Young Scientists(Startup)#21K20766);AMED-CREST(JP22gm1810002)from the Japan Agency for Medical Research and Development;FOREST(JPMJFR225X)from JST;TERUMO Life Science Foundation;Kato Memorial Bioscience Foundation;Hamaguchi Foundation for the Advancement of Biochemistry;Takeda Science Foundation;Mochida Memorial Foundation for Medical and Pharmaceutical Research;Kishimoto Foundation;Uehara Memorial Foundation;Cell Science Research Foundation;Astellas Foundation for Research on Metabolic Disorders;MSD Life Science Foundation;Public Interest Incorporated Foundation;NAGASE Science Technology Foundation;Canon Foundation;ONO Medical Research Foundation;Princess Takamatsu Cancer Research Fund.

摘　　要：T helper 9(Th9)cells are interleukin 9(IL-9)-producing cells that have diverse functions ranging from antitumor immune responses to allergic inflammation.Th9 cells differentiate from naïve CD4+T cells in the presence of IL-4 and transforming growth factor-beta(TGF-β);however,our understanding of the molecular basis of their differentiation remains incomplete.Previously,we reported that the differentiation of another subset of TGF-β–driven T helper cells,Th17 cells,is highly dependent on de novo lipid biosynthesis.On the basis of these findings,we hypothesized that lipid metabolism may also be important for Th9 cell differentiation.We therefore investigated the differentiation and function of mouse and human Th9 cells in vitro under conditions of pharmacologically or genetically induced deficiency of the intracellular fatty acid content and in vivo in mice genetically deficient in acetyl-CoA carboxylase 1(ACC1),an important enzyme for fatty acid biosynthesis.Both the inhibition of de novo fatty acid biosynthesis and the deprivation of environmental lipids augmented differentiation and IL-9 production in mouse and human Th9 cells.Mechanistic studies revealed that the increase in Th9 cell differentiation was mediated by the retinoic acid receptor and the TGF-β–SMAD signaling pathways.Upon adoptive transfer,ACC1-inhibited Th9 cells suppressed tumor growth in murine models of melanoma and adenocarcinoma.Together,our findings highlight a novel role of fatty acid metabolism in controlling the differentiation and in vivo functions of Th9 cells.

关 键 词：Th9 cell immunometabolism omics analysis fatty acid RARa anti-tumor effect 

分 类 号：R730.3[医药卫生—肿瘤]