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Enriched pathways in gut microbiome predict response to immune checkpoint inhibitor treatment across demographic regions and various cancer types
Xunhui Cai (Tongji Hospital, Huazhong University of Science and Technology), Jennifer Y. Cho (University of California, Riverside), Lijun Chen (Tongji Hospital, Huazhong University of Science and Technology), Yufeng Liu (Huazhong University of Science and Technology), Fenghu Ji (Huazhong University of Science and Technology), Katia Salgado (University of California, Riverside), Shengxiang Ge (University of California, Riverside), Dehua Yang (Chinese Academy of Sciences, Shanghai Institute of Materia Medica), Hui Yu (Wuhan Children's Hospital, Huazhong University of Science and Technology), Jianbo Shao (Wuhan Children's Hospital), P. Andrew Futreal (The University of Texas MD Anderson Cancer Center), Boris Sepesi (The University of Texas MD Anderson Cancer Center), Don Lynn Gibbons (The University of Texas MD Anderson Cancer Center), Yaobing Chen (Tongji Hospital, Huazhong University of Science and Technology), Guoping Wang (Tongji Hospital, Huazhong University of Science and Technology), Chao Cheng (Baylor College of Medicine), Meng Wu (Harvard University), Jianjun J. Zhang (The University of Texas MD Anderson Cancer Center), Ansel Hsiao (University of California, Riverside), Tian Xia (Tongji Hospital, Huazhong University of Science and Technology)
Abstract: Understanding the effect of gut microbiota function on immune checkpoint inhibitor (ICI) responses is urgently needed. Here, we integrated 821 fecal metagenomes from 12 datasets to identify differentially abundant genes and construct random forest models to predict ICI response. Gene markers demonstrated excellent predictive performance, with an average area under the curve (AUC) of 0.810. Pathway analyses revealed that quorum sensing (QS), ABC transporters, flagellar assembly, and amino acid biosynthesis pathways were enriched between responders (R) and non-responders (NRs) across 12 datasets. Furthermore, luxS , manA , fliC , and trpB exhibited consistent changes between R and NR across 12 datasets. Follow-up microbiota transplant experiments showed that inter-species signaling by different QS autoinducer-2 (AI-2) molecules (synthesized by luxS ) can act on overall community function to promote the colonization of Akkermansia muciniphila , which is associated with superior ICI responses. Together, our data highlight the role of gut microbiota function in modulating the microbiome and antitumor immunity.