Impact of intratumoral microbiome on tumor immunity and prognosis in human pancreatic ductal adenocarcinoma.

Major driver gene alteration Pancreatic ductal adenocarcinoma Prognosis Tumor microbiome Tumor-infiltrating lymphocytes

Journal

Journal of gastroenterology

ISSN: 1435-5922

Titre abrégé: J Gastroenterol

Pays: Japan

ID NLM: 9430794

Informations de publication

Date de publication:
20 Jan 2024

Historique:

received: 23 07 2023

accepted: 17 12 2023

medline: 20 1 2024

pubmed: 20 1 2024

entrez: 19 1 2024

Statut: aheadofprint

Résumé

Recent evidence suggests that the presence of microbiome within human pancreatic ductal adenocarcinoma (PDAC) tissue potentially influences cancer progression and prognosis. However, the significance of tumor-resident microbiome remains unclear. We aimed to elucidate the impact of intratumoral bacteria on the pathophysiology and prognosis of human PDAC. The presence of intratumoral bacteria was assessed in 162 surgically resected PDACs using quantitative polymerase chain reaction (qPCR) and in situ hybridization (ISH) targeting 16S rRNA. The intratumoral microbiome was explored by 16S metagenome sequencing using DNA extracted from formalin-fixed paraffin-embedded tissues. The profile of intratumoral bacteria was compared with clinical information, pathological findings including tumor-infiltrating T cells, tumor-associated macrophage, fibrosis, and alterations in four main driver genes (KRAS, TP53, CDKN2A/p16, SMAD4) in tumor genomes. The presence of intratumoral bacteria was confirmed in 52 tumors (32%) using both qPCR and ISH. The 16S metagenome sequencing revealed characteristic bacterial profiles within these tumors, including phyla such as Proteobacteria and Firmicutes. Comparison of bacterial profiles between cases with good and poor prognosis revealed a significant positive correlation between a shorter survival time and the presence of anaerobic bacteria such as Bacteroides, Lactobacillus, and Peptoniphilus. The abundance of these bacteria was correlated with a decrease in the number of tumor-infiltrating T cells positive for CD4, CD8, and CD45RO. Intratumoral infection of anaerobic bacteria such as Bacteroides, Lactobacillus, and Peptoniphilus is correlated with the suppressed anti-PDAC immunity and poor prognosis.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

The presence of intratumoral bacteria was assessed in 162 surgically resected PDACs using quantitative polymerase chain reaction (qPCR) and in situ hybridization (ISH) targeting 16S rRNA. The intratumoral microbiome was explored by 16S metagenome sequencing using DNA extracted from formalin-fixed paraffin-embedded tissues. The profile of intratumoral bacteria was compared with clinical information, pathological findings including tumor-infiltrating T cells, tumor-associated macrophage, fibrosis, and alterations in four main driver genes (KRAS, TP53, CDKN2A/p16, SMAD4) in tumor genomes.

RESULTS RESULTS

The presence of intratumoral bacteria was confirmed in 52 tumors (32%) using both qPCR and ISH. The 16S metagenome sequencing revealed characteristic bacterial profiles within these tumors, including phyla such as Proteobacteria and Firmicutes. Comparison of bacterial profiles between cases with good and poor prognosis revealed a significant positive correlation between a shorter survival time and the presence of anaerobic bacteria such as Bacteroides, Lactobacillus, and Peptoniphilus. The abundance of these bacteria was correlated with a decrease in the number of tumor-infiltrating T cells positive for CD4, CD8, and CD45RO.

CONCLUSIONS CONCLUSIONS

Intratumoral infection of anaerobic bacteria such as Bacteroides, Lactobacillus, and Peptoniphilus is correlated with the suppressed anti-PDAC immunity and poor prognosis.

Identifiants

DOI: 10.1007/s00535-023-02069-5 PMID: 38242997

pubmed: 38242997

doi: 10.1007/s00535-023-02069-5

pii: 10.1007/s00535-023-02069-5

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

Références

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

doi: 10.3322/caac.21590 pubmed: 31912902

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

doi: 10.1038/nm.3394 pubmed: 24202395 pmcid: 3954707

Yao W, Maitra A, Ying H. Recent insights into the biology of pancreatic cancer. EBioMedicine. 2020;53:102655.

doi: 10.1016/j.ebiom.2020.102655 pubmed: 32139179 pmcid: 7118569

Foucher ED, Ghigo C, Chouaib S, et al. Pancreatic ductal adenocarcinoma: a strong imbalance of good and bad immunological cops in the tumor microenvironment. Front Immunol. 2018;9:1044.

doi: 10.3389/fimmu.2018.01044 pubmed: 29868007 pmcid: 5960705

Neesse A, Algül H, Tuveson DA, et al. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut. 2015;64:1476–84.

doi: 10.1136/gutjnl-2015-309304 pubmed: 25994217

Chen Y, Kim J, Yang S, et al. Type I collagen deletion in αSMA(+) myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell. 2021;39:548–65.e6.

Yu M, Tannock IF. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell. 2012;21:327–9.

doi: 10.1016/j.ccr.2012.03.002 pubmed: 22439929

Pushalkar S, Hundeyin M, Daley D, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8:403–16.

doi: 10.1158/2159-8290.CD-17-1134 pubmed: 29567829 pmcid: 6225783

Del Castillo E, Meier R, Chung M, et al. The microbiomes of pancreatic and duodenum tissue overlap and are highly subject specific but differ between pancreatic cancer and noncancer subjects. Cancer Epidemiol Biomarkers Prev. 2019;28:370–83.

doi: 10.1158/1055-9965.EPI-18-0542 pubmed: 30373903

Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357:1156–60.

doi: 10.1126/science.aah5043 pubmed: 28912244 pmcid: 5727343

Riquelme E, Zhang Y, Zhang L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178:795–806.e12.

Kim SW, Suda W, Kim S, et al. Robustness of gut microbiota of healthy adults in response to probiotic intervention revealed by high-throughput pyrosequencing. DNA Res. 2013;20:241–53.

doi: 10.1093/dnares/dst006 pubmed: 23571675 pmcid: 3686430

Bolyen E, Rideout JR, Dillon MR, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37:852–7.

doi: 10.1038/s41587-019-0209-9 pubmed: 31341288 pmcid: 7015180

Callahan BJ, McMurdie PJ, Rosen MJ, et al. DADA2: high-resolution sample inference from Illumina amplicon data. Nat Methods. 2016;13:581–3.

doi: 10.1038/nmeth.3869 pubmed: 27214047 pmcid: 4927377

Davis NM, Proctor DM, Holmes SP, et al. Simple statistical identification and removal of contaminant sequences in marker-gene and metagenomics data. Microbiome. 2018;6:226.

doi: 10.1186/s40168-018-0605-2 pubmed: 30558668 pmcid: 6298009

Segata N, Izard J, Waldron L, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12:R60.

doi: 10.1186/gb-2011-12-6-r60 pubmed: 21702898 pmcid: 3218848

Tanaka T, Masuda A, Inoue J, et al. Integrated analysis of tertiary lymphoid structures in relation to tumor-infiltrating lymphocytes and patient survival in pancreatic ductal adenocarcinoma. J Gastroenterol. 2023;58:277–91.

doi: 10.1007/s00535-022-01939-8 pubmed: 36705749

Chen Z, Zhang S, Dong S, et al. Association of the microbiota and pancreatic cancer: opportunities and limitations. Front Immunol. 2022;13: 844401.

doi: 10.3389/fimmu.2022.844401 pubmed: 35309293 pmcid: 8928443

Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368:973–80.

doi: 10.1126/science.aay9189 pubmed: 32467386 pmcid: 7757858

Thomas RM, Gharaibeh RZ, Gauthier J, et al. Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models. Carcinogenesis. 2018;39:1068–78.

doi: 10.1093/carcin/bgy073 pubmed: 29846515 pmcid: 6067127

Lafaro KJ, Melstrom LG. The paradoxical web of pancreatic cancer tumor microenvironment. Am J Pathol. 2019;189:44–57.

doi: 10.1016/j.ajpath.2018.09.009 pubmed: 30558722 pmcid: 6315325

Zhang Y, Zoltan M, Riquelme E, et al. Immune cell production of interleukin 17 induces stem cell features of pancreatic intraepithelial neoplasia cells. Gastroenterology. 2018;155:210–23.e3.

Das S, Shapiro B, Vucic EA, et al. Tumor cell-derived Il1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 2020;80:1088–101.

doi: 10.1158/0008-5472.CAN-19-2080 pubmed: 31915130 pmcid: 7302116

Balachandran VP, Łuksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551:512–6.

doi: 10.1038/nature24462 pubmed: 29132146 pmcid: 6145146

Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.

doi: 10.1126/science.aan4236 pubmed: 29097493

Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–9.

doi: 10.1126/science.aac4255 pubmed: 26541606 pmcid: 4873287

Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.

Sethi V, Kurtom S, Tarique M, et al. Gut microbiota promotes tumor growth in mice by modulating immune response. Gastroenterology. 2018;155:33–7.e6.

Ye LY, Zhang Q, Bai XL, et al. Hypoxia-inducible factor 1alpha expression and its clinical significance in pancreatic cancer: a meta-analysis. Pancreatology. 2014;14:391–7.

doi: 10.1016/j.pan.2014.06.008 pubmed: 25278309

Tan Z, Xu J, Zhang B, et al. Hypoxia: a barricade to conquer the pancreatic cancer. Cell Mol Life Sci. 2020;77:3077–83.

doi: 10.1007/s00018-019-03444-3 pubmed: 31907561

Gnanasekaran J, Binder Gallimidi A, Saba E, et al. Intracellular Porphyromonas gingivalis promotes the tumorigenic behavior of pancreatic carcinoma cells. Cancers (Basel). 2020;12:2331.

doi: 10.3390/cancers12082331 pubmed: 32824786

Harada Y, Sujino T, Miyamoto K, et al. Intracellular metabolic adaptation of intraepithelial CD4

Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 2015;1:653–61.

doi: 10.1001/jamaoncol.2015.1377 pubmed: 26181352 pmcid: 4537376

Hezaveh K, Shinde RS, Klötgen A, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity. 2022;55:324–40.e8.

Hayashi M, Ikenaga N, Nakata K, et al. Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis. Cancer Sci. 2023;114:3666–78.

doi: 10.1111/cas.15901 pubmed: 37438965 pmcid: 10475786

Tan Q, Ma X, Yang B, et al. Periodontitis pathogen Porphyromonas gingivalis promotes pancreatic tumorigenesis via neutrophil elastase from tumor-associated neutrophils. Gut Microbes. 2022;14:2073785.

doi: 10.1080/19490976.2022.2073785 pubmed: 35549648 pmcid: 9116393