{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:02:40Z","timestamp":1788670960688,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"INSERM","award":["ANR-17-CE15-0020-01"],"award-info":[{"award-number":["ANR-17-CE15-0020-01"]}]},{"name":"CNRS","award":["ANR-17-CE15-0020-01"],"award-info":[{"award-number":["ANR-17-CE15-0020-01"]}]},{"name":"University of Lille","award":["ANR-17-CE15-0020-01"],"award-info":[{"award-number":["ANR-17-CE15-0020-01"]}]},{"name":"Pasteur Institute of Lille","award":["ANR-17-CE15-0020-01"],"award-info":[{"award-number":["ANR-17-CE15-0020-01"]}]},{"name":"Agence Nationale de la Recherche","award":["ANR-17-CE15-0020-01"],"award-info":[{"award-number":["ANR-17-CE15-0020-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-conventional T cells, such as \u03b3\u03b4 T and invariant natural killer T (iNKT) cells, are emerging players in fighting cancer. Alpha-galactosylceramide (\u03b1-GalCer) is used as an exogenous ligand to activate iNKT cells. Human cells don\u2019t have a direct pathway producing \u03b1-GalCer, which, however, can be produced by bacteria. We searched the literature for bacteria strains that are able to produce \u03b1-GalCer and used available sequencing data to analyze their presence in human tumor tissues and their association with survival. The modulatory effect of antibiotics on the concentration of \u03b1-GalCer was analyzed in mice. The human gut bacteria Bacteroides fragilis, Bacteroides vulgatus, and Prevotella copri produce \u03b1-GalCer structures that are able to activate iNKT cells. In mice, \u03b1-GalCer was depleted upon treatment with vancomycin. The three species were detected in colon adenocarcinoma (COAD) and rectum adenocarcinoma tissues, and Prevotella copri was also detected in bone tumors and glioblastoma tissues. Bacteroides vulgatus in COAD tissues correlated with better survival. In conclusion, \u03b1-GalCer-producing bacteria are part of the human gut microbiome and can infiltrate tumor tissues. These results suggest a new mechanism of interaction between bacteria and immune cells: \u03b1-GalCer produced by bacteria may activate non-conventional T cells in tumor tissues, where they can exert a direct or indirect anti-tumor activity.<\/jats:p>","DOI":"10.3390\/ijms23115896","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:04:06Z","timestamp":1653429846000},"page":"5896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Interaction between Bacteria and the Immune System for Cancer Immunotherapy: The \u03b1-GalCer Alliance"],"prefix":"10.3390","volume":"23","author":[{"given":"Arsenij","family":"Ustjanzew","sequence":"first","affiliation":[{"name":"Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6379-4317","authenticated-orcid":false,"given":"Valentin","family":"Sencio","sequence":"additional","affiliation":[{"name":"Centre d\u2019Infection et d\u2019Immunit\u00e9 de Lille, Inserm U1019, CNRS UMR 8204, University of Lille, CHU Lille, Institut Pasteur de Lille, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3373-1814","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Trottein","sequence":"additional","affiliation":[{"name":"Centre d\u2019Infection et d\u2019Immunit\u00e9 de Lille, Inserm U1019, CNRS UMR 8204, University of Lille, CHU Lille, Institut Pasteur de Lille, 59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5432-8234","authenticated-orcid":false,"given":"J\u00f6rg","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Sandhoff","sequence":"additional","affiliation":[{"name":"Lipid Pathobiochemistry, German Cancer Research Center, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9094-1634","authenticated-orcid":false,"given":"Claudia","family":"Paret","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology\/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.immuni.2018.03.009","article-title":"Unconventional T Cell Targets for Cancer Immunotherapy","volume":"48","author":"Godfrey","year":"2018","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.immuni.2014.08.017","article-title":"The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian \u03b1-Linked Glycosylceramides","volume":"41","author":"Kain","year":"2014","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.molimm.2015.06.009","article-title":"Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides","volume":"68","author":"Kain","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.4049\/jimmunol.1103582","article-title":"Role of gammadelta T cells in al-pha-galactosylceramide-mediated immunity","volume":"188","author":"Paget","year":"2012","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.clim.2010.10.005","article-title":"Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans","volume":"140","author":"Metelitsa","year":"2011","journal-title":"Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1428156","DOI":"10.1080\/2162402X.2018.1428156","article-title":"Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells","volume":"7","author":"Dockry","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.canlet.2014.10.002","article-title":"Thymosin alpha1 enhanced cytotoxicity of iNKT cells against colon cancer via upregulating CD1d expression","volume":"356","author":"Ni","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"533","DOI":"10.3389\/fimmu.2019.00533","article-title":"Regulatory T Cells and Plasmacytoid Dendritic Cells Within the Tumor Microenvironment in Gastric Cancer Are Correlated With Gastric Microbiota Dysbiosis: A Preliminary Study","volume":"10","author":"Ling","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejca.2021.03.053","article-title":"Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma","volume":"151","author":"Zhu","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/s13046-021-02128-w","article-title":"The role of the tumor microbe microenvironment in the tumor immune microenvironment: Bystander, activator, or inhibitor?","volume":"40","author":"Ma","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1186\/s40425-019-0775-x","article-title":"Antibiotic therapy and outcome from immune-checkpoint inhibitors","volume":"7","author":"Pinato","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"The Human Microbiome Project Consortium (2012). Structure, function and diversity of the healthy human microbiome. Nature, 486, 207\u2013214.","DOI":"10.1038\/nature11234"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.chom.2020.12.001","article-title":"The cancer microbiome atlas: A pan-cancer comparative analysis to distinguish tissue-resident microbiota from contaminants","volume":"29","author":"Dohlman","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s13238-020-00813-8","article-title":"Unexpected guests in the tumor microenvironment: Microbiome in cancer","volume":"12","author":"Wei","year":"2021","journal-title":"Protein Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"604531","DOI":"10.3389\/fonc.2020.604531","article-title":"Research Progress of Pancreas-Related Microorganisms and Pancreatic Cancer","volume":"10","author":"Zhang","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kazim, S.F., Martinez, E., Hough, T.J., Spangler, B.Q., Bowers, C.A., and Chohan, M.O. (2021). The Survival Benefit of Postoperative Bacterial Infections in Patients With Glioblastoma Multiforme: Myth or Reality?. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.615593"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1021\/jm00012a018","article-title":"Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice","volume":"38","author":"Morita","year":"1995","journal-title":"J. Med. Chem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1002\/1873-3468.13114","article-title":"Emerging concepts of ganglioside metabolism","volume":"592","author":"Sandhoff","year":"2018","journal-title":"FEBS Lett."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wieland Brown, L.C., Penaranda, C., Kashyap, P.C., Williams, B.B., Clardy, J., Kronenberg, M., Sonnenburg, J.L., Comstock, L.E., Bluestone, J.A., and Fischbach, M.A. (2013). Production of alpha-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001610"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1194\/jlr.D076190","article-title":"Diastereomer-specific quantification of bioactive hexosylceramides from bacteria and mammals","volume":"58","author":"Schlosser","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1194\/jlr.RA119000236","article-title":"Bacterial immunogenic alpha-galactosylceramide identified in the murine large intestine: Dependency on diet and inflammation","volume":"60","author":"Lamprecht","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1126\/science.aay9189","article-title":"The human tumor microbiome is composed of tumor type-specific intracellular bacteria","volume":"368","author":"Nejman","year":"2020","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","article-title":"The biology of NKT cells","volume":"25","author":"Bendelac","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41586-021-03368-8","article-title":"Identification of bacteria-derived HLA-bound peptides in melanoma","volume":"592","author":"Kalaora","year":"2021","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.3389\/fimmu.2020.01819","article-title":"Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells","volume":"11","author":"Lehmann","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41598-020-79874-y","article-title":"Metagenomic analysis of formalin-fixed paraffin-embedded tumor and normal mucosa reveals differences in the microbiome of colorectal cancer patients","volume":"11","author":"Castillejo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.3389\/fgene.2019.00213","article-title":"Inferring Bacterial Infiltration in Primary Colorectal Tumors From Host Whole Genome Sequencing Data","volume":"10","author":"Guo","year":"2019","journal-title":"Front. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11","DOI":"10.23922\/jarc.2020-064","article-title":"Immunotherapy in Colorectal Cancer: Current and Future Strategies","volume":"5","author":"Ooki","year":"2021","journal-title":"J. Anus. Rectum. Colon."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3892\/mco.2021.2255","article-title":"Prognostic factors of survival in stage IV colorectal cancer with synchronous liver metastasis: Negative effect of the KRAS mutation","volume":"14","author":"Nunez","year":"2021","journal-title":"Mol. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/bjc.2011.19","article-title":"BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer","volume":"104","author":"Yokota","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3644","DOI":"10.1038\/s41467-020-17386-z","article-title":"Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival","volume":"11","author":"Zaidi","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Miyakawa, T., Kawamura, H., Honda, M., Takano, Y., Kinuta, S., Kamiga, T., Yamazaki, S., Muto, A., Shiraso, S., and Yamashita, N. (2022). Impact of histological subtype on prognosis in stage IV colorectal cancer: A population-based cohort study. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0264652"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8154","DOI":"10.1038\/s41598-021-87486-3","article-title":"Enhancing the landscape of colorectal cancer using targeted deep sequencing","volume":"11","author":"Lee","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"707734","DOI":"10.3389\/fimmu.2021.707734","article-title":"Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies","volume":"12","author":"Chasov","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7322","DOI":"10.1158\/1078-0432.CCR-05-0877","article-title":"Increased intratumor Valpha24-positive natural killer T cells: A prognostic factor for primary colorectal carcinomas","volume":"11","author":"Tachibana","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e00587-18","DOI":"10.1128\/mSphere.00587-18","article-title":"The Protective Role of Bacteroides fragilis in a Murine Model of Colitis-Associated Colorectal Cancer","volume":"3","author":"Lee","year":"2018","journal-title":"mSphere"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1126\/science.aad1329","article-title":"Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota","volume":"350","author":"Vetizou","year":"2015","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.jtho.2019.04.007","article-title":"The Diversity of Gut Microbiome is Associated with Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients with NSCLC","volume":"14","author":"Jin","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1136\/gutjnl-2020-321031","article-title":"Ginseng polysaccharides alter the gut microbiota and kynurenine\/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1\/programmed cell death ligand 1 (anti-PD-1\/PD-L1) immunotherapy","volume":"71","author":"Huang","year":"2022","journal-title":"Gut"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s40425-019-0658-1","article-title":"Role of antibiotic use, plasma citrulline and blood microbiome in advanced non-small cell lung cancer patients treated with nivolumab","volume":"7","author":"Dumenil","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_41","unstructured":"Therneau, T. (2022, May 23). A Package for Survival Analysis in R. R Package Version 3.3-1. Available online: https:\/\/CRAN.R-project.org\/package=survival."},{"key":"ref_42","unstructured":"Kassambara, A., Kosinski, M., Biecek, P., and Fabian, S. (2022, May 23). Package \u2018survminer\u2019. Drawing Survival Curves Using \u2018ggplot2\u2019 (R package version 0.4.9). Available online: https:\/\/CRAN.R-project.org\/package=survminer."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5896\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:17:59Z","timestamp":1760138279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23115896"],"URL":"https:\/\/doi.org\/10.3390\/ijms23115896","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,24]]}}}