19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

          Related collections

          Most cited references43

          • Record: found
          • Abstract: found
          • Article: not found

          Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

          Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

            Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients

              Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                15 July 2022
                2022
                : 13
                : 874922
                Affiliations
                [1] 1 School of Medicine, Shenzhen Campus of Sun Yat-Sen University , Shenzhen, China
                [2] 2 Department of Research and Development, Shenzhen Xbiome Biotech Co. Ltd. , Shenzhen, China
                [3] 3 Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-Sen University , Shenzhen, China
                Author notes

                Edited by: Marina De Bernard, University of Padua, Italy

                Reviewed by: Yong Yang, China Pharmaceutical University, China; Chao Jiang, Zhejiang University, China; Jingxin Li, Shandong University, China; Ning-Ning Liu, Shanghai Jiao Tong University, China

                *Correspondence: Yiming Yin, yinyiming@ 123456xbiome.com ; Wenjing Zhao, zhaowj29@ 123456ms.sysu.edu.cn

                †These authors have contributed equally to this work

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2022.874922
                9336524
                35911731
                04abfe05-4485-4123-a006-1021cadf425f
                Copyright © 2022 Huang, Zheng, Kang, Hao, Mao, Zhang, Chen, Tan, He, Zhao and Yin

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 February 2022
                : 27 June 2022
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 43, Pages: 11, Words: 4188
                Funding
                Funded by: National Key Research and Development Program of China , doi 10.13039/501100012166;
                Categories
                Immunology
                Original Research

                Immunology
                fecal microbiota transplantation,anti-pd-1 therapy,immunotherapy,colorectal cancer,bacteroides

                Comments

                Comment on this article