The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
复制标题
DOI：
10.1126/sciimmunol.abn0704
复制
发表时间：
2022-09-09
影响因子：
24.8
通讯作者：
Shinde, Rahul S.
中科院分区：
文献类型：
--
作者：
Mirji, Gauri;Worth, Alison;Bhat, Sajad Ahmad;El Sayed, Mohamed;Kannan, Toshitha;Goldman, Aaron R.;Tang, Hsin-Yao;Liu, Qin;Auslander, Noam;Dang, Chi, V;Abdel-Mohsen, Mohamed;Kossenkov, Andrew;Stanger, Ben Z.;Shinde, Rahul S.
肠道微生物组的组成可以控制先天和适应性免疫，并已成为肿瘤生长的关键调节剂，特别是在免疫检查点阻断（ICB）治疗的背景下。然而，微生物组如何影响肿瘤生长的潜在机制尚不清楚。胰腺导管腺癌（PDAC）往往难以治疗，包括ICB。通过非靶向、基于LC-MS/MS的代谢组学筛选，我们发现了一种肠道微生物衍生的代谢物三甲胺n-氧化物（TMAO），它可以增强对PDAC的抗肿瘤免疫。腹腔内或通过膳食胆碱补充给原位PDAC小鼠TMAO可降低肿瘤生长，并与肿瘤微环境中的免疫刺激肿瘤相关巨噬细胞（TAM）表型和激活效应T细胞反应相关。在机制上，TMAO增强了i型干扰素（IFN）途径，并以i型IFN依赖的方式赋予抗肿瘤作用。值得注意的是，静脉注射tmao引发的巨噬细胞产生类似的抗肿瘤作用。在PDAC小鼠模型中，TMAO与ICB（抗pd1和/或抗tim3）联合使用可显著降低肿瘤负荷，提高生存率，优于单独使用TMAO或ICB。最后，含有CutC（一种产生三甲胺的酶，氧化三甲胺前体）的细菌水平与PDAC患者的长期生存和黑色素瘤患者抗pd1反应的改善相关。总之，我们的研究确定了肠道微生物代谢物TMAO作为抗肿瘤免疫的驱动因素，并为针对TMAO的潜在治疗策略奠定了基础。微生物代谢物三甲胺n -氧化物（TMAO）缓解胰腺癌肿瘤微环境中的免疫抑制。
The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome impacts tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a non-targeted, LC-MS/MS based metabolomic screen, we identified a gut microbe-derived metabolite trimethylamine N-oxide (TMAO) that enhanced anti-tumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC bearing mice reduced tumor growth and associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated type-I interferon (IFN) pathway and conferred anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages intravenously produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in PDAC patients and improved response to anti-PD1 in melanoma patients. Together, our study identifies the gut microbial metabolite TMAO as a driver of anti-tumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO. The microbial metabolite trimethylamine N-oxide (TMAO) relieves immunosuppression in the tumor microenvironment of pancreatic cancer.
登录
查看更多内容
影响因子：
11.2
作者：
Bae S;Ulrich CM;Neuhouser ML;Malysheva O;Bailey LB;Xiao L;Brown EC;Cushing-Haugen KL;Zheng Y;Cheng TY;Miller JW;Green R;Lane DS;Beresford SA;Caudill MA
通讯作者：
Caudill MA
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
使用流式细胞仪分析小鼠组织中的骨髓细胞
影响因子：
--
作者：
Liu Z;Gu Y;Shin A;Zhang S;Ginhoux F
通讯作者：
Ginhoux F
影响因子：
32.4
作者：
Hezaveh K;Shinde RS;Klötgen A;Halaby MJ;Lamorte S;Ciudad MT;Quevedo R;Neufeld L;Liu ZQ;Jin R;Grünwald BT;Foerster EG;Chaharlangi D;Guo M;Makhijani P;Zhang X;Pugh TJ;Pinto DM;Co IL;McGuigan AP;Jang GH;Khokha R;Ohashi PS;O'Kane GM;Gallinger S;Navarre WW;Maughan H;Philpott DJ;Brooks DG;McGaha TL
通讯作者：
McGaha TL
影响因子：
64.5
作者：
Lam KC;Araya RE;Huang A;Chen Q;Di Modica M;Rodrigues RR;Lopès A;Johnson SB;Schwarz B;Bohrnsen E;Cogdill AP;Bosio CM;Wargo JA;Lee MP;Goldszmid RS
通讯作者：
Goldszmid RS