Immunology, Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA, USA.
Bioinformatics Facility, the Wistar Institute, Philadelphia, PA, USA.
Sci Immunol. 2022 Sep 9;7(75):eabn0704. doi: 10.1126/sciimmunol.abn0704.
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 affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography-tandem mass spectrometry-based metabolomic screen, we identified the gut microbe-derived metabolite trimethylamine -oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN-dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor 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. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO.
肠道微生物组的组成可以控制先天和适应性免疫，并且已成为肿瘤生长的关键调节剂，尤其是在免疫检查点阻断（ICB）治疗的情况下。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）往往对治疗具有抗性，包括 ICB。我们使用非靶向、基于液相色谱-串联质谱的代谢组学筛选方法，鉴定出肠道微生物衍生的代谢物三甲胺氧化物（TMAO），它增强了对 PDAC 的抗肿瘤免疫。将 TMAO 腹膜内或通过饮食胆碱补充剂递送至原位 PDAC 荷瘤小鼠可减少肿瘤生长，与免疫刺激的肿瘤相关巨噬细胞（TAM）表型相关，并在肿瘤微环境中激活效应 T 细胞反应。从机制上讲，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。静脉内递送 TMAO 激活的巨噬细胞可产生类似的抗肿瘤作用。在 PDAC 的小鼠模型中，将 TMAO 与 ICB（抗 PD1 和/或抗 Tim3）联合使用可显著降低肿瘤负担，并提高生存率，优于 TMAO 或 ICB 单独使用。最后，含有 CutC（产生 TMAO 前体三甲胺的酶）的细菌水平与 PDAC 患者的长期生存相关，并改善了黑色素瘤患者对抗 PD1 的反应。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，并为靶向 TMAO 的潜在治疗策略奠定了基础。
