Phagocytes as Trojan horse for Fusobacterium nucleatum routing to the tumor tissues and enhance tumor metastasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243383 | GEO | 2024/01/01
REPOSITORIES: GEO
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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:Although membrane-anchored PD-L1 has been well-studied for its engagement with PD-1 on T cells to evade anti-tumor immunity, whether PD-L1 regulate oncogenic signaling pathways in tumor cells remains elusive. We found that a portion of PD-L1 could translocate to the nucleus and knockout of PD-L1 changed RNA profiles in MDA-MB-231 cells. To further explore potential role of PD-L1 in regulating gene expression in tumor cells, we performed ChIP-seq in HA tag-inserted (after the signal peptide) PD-L1 re-expressed MBA-MB-231cells (endogenous PD-L1 knockout background). Methods: HA-insert-PD-L1 was re-introduced into MDA-MB-231 PD-L1 knockout cells using lentivirus and then the infected cells were selected with puromycin to make stable subclones. ChIP experiments were performed using HA antibody (Abcam, ab9110). Conclusions: Our study indicates that nuclear PD-L1 has potential roles in regulating gene transcription. More efforts are needed to further dissect the exact working model.
2020-06-07 | GSE146648 | GEO
Project description:Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites’ replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors. Comparison of 4 different RNA pools with a 2-Color-Loop Design including 10 microarrays: [1] T. gondii infected and IFN-gamma treated, [2] T. gondii infected and untreated, [3] Non-infected and IFN-gamma treated, and [4] Non-infected and untreated.
2012-01-25 | E-GEOD-28499 | biostudies-arrayexpress
Project description:Aim: The aim of this study is to explore the impact of Pien Tze Huang (PZH) on enhancing T cell cytotoxicity by modulating colorectal cancer stem cell (CRC-CSC) markers, programmed death protein ligand-1 (PD-L1), and the transcription factor signal transducer and activator of transcription 3 (STAT3) protein expression in vivo, ex vivo, and in vitro. Methods: HCT116, HCT15, and SW480 cell lines were subjected to treatment with PZH, followed by assessment of cell viability and stemness through CCK8 and spheroid formation assays. Western blot and immunofluorescence techniques were employed to evaluate the expression levels of stem cell markers (DCLK1, CD133, CD44, MET, and LGR5), PD-L1, and STAT3 across three CRC cell lines and five patient-derived organoids (PDOs). Flow cytometry and western blot analyses were utilized to validate T cell expansion from both donors and CRC patients. CRC cells and CRC-PDOs, pre-treated with PZH, were co-cultured with expanded T cells from both donor and autologous peripheral blood mononuclear cells (PBMCs) respectively. The viability of CRC cells and PDOs was evaluated through Calcein-AM staining to measure fluorescence intensity and cell count following co-culture. In the syngeneic MC38 C57BL/6 xenograft model, tumor growth curve and body weight were monitored subsequent to treatment with PZH, anti-PD-1, and PZH combined with anti-PD-1. Immunohistochemistry was performed to assess protein levels of CD133, CD44, STAT3, PD-L1, CD8, and IL-6R in tumor tissue. Results: The effectiveness of PZH in reducing CRC cell viability and suppressing stemness markers, such as LGR5, CD44, MET, DCLK1, and CD133, is evident. PZH also displayed inhibitory effects on tumorigenesis in five CRC-PDOs, with varying sensitivity across cases (3 sensitive and 2 less sensitive). Moreover, PZH enhanced the cytotoxicity of donor T cells against CRC cells and rectified the cytotoxic deficiency or bolstered the cytotoxicity of autologous T cells against CRC-PDOs by downregulating PD-L1 and STAT3 protein expressi Conclusion: PZH enhances T cell-mediated killing effect by inhibiting CRC stem cell markers, PD-L1, and STAT3. Key Words: Pien Tze Huang, patient-derived organoid, colorectal cancer stem cells, programmed death protein ligand-1, signal transducer and activator of transcription 3
2024-05-06 | GSE265991 | GEO
Project description:This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRCTo investigate the potential of NFKB2 as a therapeutic target for colorectal cancer (CRC), we conducted a systematic analysis of the molecular mechanism and function of NFKB2 in CRC. VariousA range of experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtaingain a deeper understanding of the regulation of NFKB2 in CRC. TheOur results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasismetastases of CRC. NFKB2 played an importanta role in promoting tumor growth through CD8+ T cell exhaustion. MoreoverAdditionally, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2)STAT2, leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1)PD-L1 expression. Applying aThe application of a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 (PD-1)PD-1 blockade-based immunotherapy. In conclusion,These findings suggest that the facilitated NFKB2-STAT2/PD-L1 axis may suppresses immune surveillance in CRC and targeting NFKB2 maycould enhance the efficacy of immunotherapeutic strategies. Our resultsThis study provides novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape. However, our findings requireand further validation of these findings in a clinical trial is needed to establish NFKB2 inhibition as a therapeutic strategy for CRC patients.
2023-12-21 | GSE250065 | GEO
Project description:Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, promoting RAB11-mediated recycling of PD-L1, and acting as a scaffold between PD-L1 and RAB11, thus replenishing its distribution on the tumor cell surface.
2021-08-15 | PXD027826 | Pride
Project description:This is a mathematical model investigating the effects of continuous and intermittent PD-L1 and anti-PD-L1 therapy upon tumor-immune dynamics.
2019-08-27 | MODEL1908270001 | BioModels
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE