Eubacterium rectale Improves the Efficacy of Anti-PD1 Immunotherapy in Melanoma via l-Serine-Mediated NK Cell Activation  

作　　者：Nian Liu Lihui Chen Mingjie Yan Qian Tao Jie Wu Jing Chen Xiang Chen Wei Zhang Cong Peng 

机构地区：[1]Department of Clinical Pharmacology,Xiangya Hospital,Central South University,Changsha,Hunan,China [2]Department of Dermatology,Xiangya Hospital,Central South University,Changsha,Hunan,China [3]Hunan Key Laboratory of Skin Cancer and Psoriasis,Xiangya Hospital,Central South University,Changsha,Hunan,China [4]Furong Laboratory,Xiangya Hospital,Central South University,Changsha,Hunan,China [5]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan,China

出　　处：《Research》2023年第4期777-792,共16页研究（英文）

基　　金：This work was supported by the National Key Research and Development Program of China(No.2021YFA1301200);the National Natural Science(grant No.82073458,82203024,8213000715,81830096,82073018,and 2022YFC2504700);the Science and Technology Innovation Program of Hunan Province(2021RC4013);the Program of Introducing Talents of Discipline to Universities(111 Project,no.B20017).

摘　　要：Natural killer(NK)cells,as key immune cells,play essential roles in tumor cell immune escape and immunotherapy.Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients;however,the details of the mechanism remain elusive.In this study,we found that Eubacterium rectale was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and that a high E.rectale abundance was related to longer survival in melanoma patients.Furthermore,administration of E.rectale remarkably improved the efficacy of anti-PD1 therapy and increased the overall survival of tumor-bearing mice;moreover,application of E.rectale led to a significant accumulation of NK cells in the tumor microenvironment.Interestingly,conditioned medium isolated from an E.rectale culture system dramatically enhanced NK cell function.Gas chromatography-mass spectrometry/ultrahigh performance liquid chromatography-tandem mass spectrometry-based metabolomic analysis showed that l-serine production was significantly decreased in the E.rectale group;moreover,administration of an l-serine synthesis inhibitor dramatically increased NK cell activation,which enhanced anti-PD1 immunotherapy effects.Mechanistically,supplementation with l-serine or application of an l-serine synthesis inhibitor affected NK cell activation through Fos/Fosl.In summary,our findings reveal the role of bacteria-modulated serine metabolic signaling in NK cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.

关 键 词：PD1 RECTAL MELANOMA 

分 类 号：R730.51[医药卫生—肿瘤]