Fusobacterium nucleatum Induces PD-L1 Expression by Tumor-Associated Macrophages and Inhibits Anti-Tumor Immunity in Colorectal Cancer.
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PROVIDER: PRJNA869691 | ENA |
REPOSITORIES: ENA
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Project description:Fusobacterium nucleatum is a Gram-negative oncobacterium that is associated with colorectal cancer. The molecular mechanisms utilized by F. nucleatum to promote colorectal tumor development have largely focused on adhesin-mediated binding to the tumor tissue and on the pro-inflammatory capacity of F. nucleatum. However, the exact manner in which F. nucleatum promotes inflammation in the tumor microenvironment and subsequent tumor promotion remains underexplored. Here, we show that both live F. nucleatum and sterile F. nucleatum-conditioned medium promote CXCL8 release from the intestinal adenocarcinoma HT-29 cell line. We determined that the pro-inflammatory response was ALPK1-dependent in both HEK293 and HT-29 cells and that the released F. nucleatum molecule had characteristics that match those of the pro-inflammatory ALPK1 ligand ADP-heptose or related heptose phosphates. In addition, not only F. nucleatum but also other Fusobacterium species such as F. varium, F. necrophorum and F. gonidiaformans promoted an ALPK1-dependent pro-inflammatory environment, indicating that ADP-heptose or related heptose phosphates secretion is a conserved feature of the Fusobacterium genus. By performing transcriptional analysis of ADP-heptose stimulated HT-29 cells, we found several inflammatory and cancer-related pathways to be differentially regulated, including DNA mismatch repair genes and the immune inhibitory receptor PD-L1. Finally, we show that stimulation of HT-29 cells with F. nucleatum resulted in an ALPK1-dependent upregulation of PD-L1. These results aid in our understanding of the mechanisms by which F. nucleatum can affect tumor development and therapy and pave the way for future therapeutic approaches.
2024-05-13 | GSE267317 | GEO
Project description:Fusobacterium nucleatum (Fn) infection has been linked to the initiation and development of colorectal cancer (CRC). However, the underlying mechanisms remains unexplored. Tissues from Fn-infected mice were first collected for single-cell RNA sequencing. we investigated the correlation between Fn infection and accumulations of tumor associated macrophages (TAMs) in tissues from human CRC or AOM/DSS treated mice. The impact of Fn on biological function of TAMs were interrogated. We deciphered the mechanisms for interaction between Fn and TAMs in CRC. We explored the impact of Fn infection on immune-checkpoint blockade (ICB) treatment in a multicohort study.The analysis of single-cell RNA sequencing revealed an enrichment of TAMs in Fn positive tissues. A significant correlation between Fn DNA level and TAMs was observed. Functionally, Fn could recruit TAMs in CRC tissues and promote their biological functions by enhancing PD-L1 expression and thus suppressing CD8+ T cells. Mechanistically, Fn infection led to increased secreted IL-6 via TLR4/MyD88/NF-κB pathways, and the activated IL-6/STAT3 pathway enhanced PD-L1 expression in TAMs. By using several mice models, we found IL-6 inhibition, loss of MyD88 or anti-PD-L1 treatment could significantly inhibit tumorigenesis. Clinically, Fn positive patients tended to be more sensitive to ICB treatment, with a better prognosis than Fn-negative patients.
2024-04-19 | GSE172334 | GEO
Project description:Fusobacterium nucleatum (Fn) infection has been linked to the initiation and development of colorectal cancer (CRC). However, the underlying mechanisms remains unexplored. Tissues from Fn-infected mice were first collected for single-cell RNA sequencing. we investigated the correlation between Fn infection and accumulations of tumor associated macrophages (TAMs) in tissues from human CRC or AOM/DSS treated mice. The impact of Fn on biological function of TAMs were interrogated. We deciphered the mechanisms for interaction between Fn and TAMs in CRC. We explored the impact of Fn infection on immune-checkpoint blockade (ICB) treatment in a multicohort study.The analysis of single-cell RNA sequencing revealed an enrichment of TAMs in Fn positive tissues. A significant correlation between Fn DNA level and TAMs was observed. Functionally, Fn could recruit TAMs in CRC tissues and promote their biological functions by enhancing PD-L1 expression and thus suppressing CD8+ T cells. Mechanistically, Fn infection led to increased secreted IL-6 via TLR4/MyD88/NF-κB pathways, and the activated IL-6/STAT3 pathway enhanced PD-L1 expression in TAMs. By using several mice models, we found IL-6 inhibition, loss of MyD88 or anti-PD-L1 treatment could significantly inhibit tumorigenesis. Clinically, Fn positive patients tended to be more sensitive to ICB treatment, with a better prognosis than Fn-negative patients.
2022-08-18 | GSE211257 | GEO
Project description:Localization of Fusobacterium nucleatum in the placenta may be associated with pregnancy complications including preeclampsia (PE), but its specific pathobiology is unknown. Our aim was to analyze the effect of Fusobacterium nucleatum on HUVEC cells to further elucidate placental dysfunction in the context of Fusobacterium nucleatum infestation.
2024-06-08 | GSE269085 | GEO
Project description:Neutrophils are known to be stimulated by different periodontal bacteria to produce reactive oxygen species and cytokines. It is inportant to investigate the gene changes made by bacteria of importance, of which, for periodontal disease, fusobaterium nucleatum is one. we used microarrays to investigate gene experssion changes in peripheral blood neutrophils werwhich e stimulated with or with out Fusobacterium Nucleatum (10953). Neutrophils from periodonatlly healthy individuals (n=4) were isolated and stimulated for 3hrs with or without fusobaterium nucleatum (10953). RNA was then extracted from these and pooled before hybridization on Affymetrix microarrays
2010-07-20 | E-GEOD-20151 | biostudies-arrayexpress
Project description:Fusobacterium nucleatum Induces PD-L1 Expression by Tumor-Associated Macrophages and Inhibits Anti-Tumor Immunity in Colorectal Cancer.
| PRJNA722987 | ENA
Project description:Fusobacterium nucleatum is a Gram-negative oral bacterial species associated with periodontal disease progression. As periodontal disease progresses, it is known F. nucleatum coaggregated with blood is frequently detected in the gingival crevice. However, it is largely unknown whether these interactions between F. nucleatum and blood induce a particular genetic response. We tested the cultures of F. nucleatum ATCC 25586 with or without blood in a semi-defined growth medium by microarray analysis and found 14 genes that were affected after only about 4hr. of adhered blood. Then, we selected 7 genes that changed significantly and tested these genes via real-time RT-PCR to confirm the validity of the microarray results. As a result, one amino sugar-binding protein on the membrane of F. nucleatum was especially expressed high via both microarray and real-time RT-PCR. Based upon these data, it appears that the protein on the F. nucleatum membrane binds and transfers the amino sugar only under blood conditions. This study aims to determine the effect of blood on the gene expression profiling of F. nucreatum. The study contains 2 separate experiments that both measure the cultures without or with blood. The samples with blood contain 9% and 33% blood.
2012-09-01 | E-GEOD-36410 | biostudies-arrayexpress
Project description:Fusobacterium nucleatum-treated LoVo cells reported an increased promoting CRC metastasis effect compared with PBS control. To understand the underlying mechanisms of Fusobacterium nucleatum-induced metastasis ability of CRC cells, we performed RNA-sequencing in LoVo cells s with or without Fusobacterium nucleatum treatment with three independent biological replicates.
2021-10-19 | GSE173549 | GEO
Project description:To investigate the effect of the Zn ionophore, PBT2, on the transcriptomic response of Fusobacterium nucleatum ATCC 25586, RNA was extracted from bacterial samples which had been treated as follows: Untreated (0.006% DMSO v/v), DMSO-Zn treated (0.006% DMSO v/v + 200 uM ZnSO4), or PBT2-Zn treated (0.125 ug/mL PBT2 + 200 uM ZnSO4) (DMSO was the vehicle control). RNA samples were collected at 0h, 0.5h, and 1h post challenge in biological triplicate and sequenced using Illumina HiSeq platform. We mapped sequences to the reference genome F. nucleatum subsp. nucleatum ATCC 25586 and performed DEseq2 analysis to determine differentially expressed genes across time and treatment.
2021-07-15 | E-MTAB-8681 | biostudies-arrayexpress
Project description:To investigate the role of Fusobacterium nucleatum-mediated m6A modification, we performed m6A-sequencing to map the m6A modification in control or Fusobacterium nucleatum-treated HCT116 cells.
2022-02-07 | GSE150308 | GEO