Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models.
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ABSTRACT:
PROVIDER: PRJNA1079672 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR28065532_1.fastq.gz | Fastqsanger.gz | |||
| SRR28065532_2.fastq.gz | Fastqsanger.gz | |||
| SRR28065533_1.fastq.gz | Fastqsanger.gz | |||
| SRR28065533_2.fastq.gz | Fastqsanger.gz | |||
| SRR28065534_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Evaluate the anti-tumorigenic efficacy and immunomodulatory effects of chitin as general blocker of immunosuppressive chitinase-like proteins (CLPs) in combination with and without anti-PD-1 immune checkpoint blockade (ICB) in an immunocompetent 4T1- and 66cl4-based intraductal model for triple-negative breast cancer (TNBC). Methods: 4T1 and 66cl4 mammary tumor-bearing female BALB/c mice were either left untreated or were treated with anti-PD-1, chitin or chitin + anti-PD-1 for 2 weeks (w) between 3 and 5 w post-inoculation (p.i.) of the mammary tumor cells. After the 2-w treatment, 4T1 and 66cl4 primary tumors were resected and RNA was isolated from the tissue using in-house developed protocols. Results: Chitin-mediated reduction in innate immunosuppression and increased anti-tumor T-cell immunity in primary tumors of both TNBC models was clearly presented at the genomic level based on RNA-sequencing analysis. More specifically, a selection of 68 and 55 innate immunity-related genes in respectively 4T1 and 66cl4 primary tumors were downregulated upon chitin treatment in combination with or without anti-PD-1. Several of the selected innate immunity genes could be linked to immunosuppressive myeloid cell types, including Ccl2, Cxcl2, Csf1r and Itgam. Genes related to T-cell exhaustion, including Pdcd1, Cd274, Havcr2 and Lag3, were downregulated upon chitin and chitin + anti-PD-1 treatment in 4T1 tumors. Chitin- and chitin + anti-PD-1-treated 66cl4 tumors showed upregulation of genes associated with enhanced T-cell activity, including Cd8a, Cd8b1, Ifng, Il12b and Il18r1. In line with an overall reduced inflammation upon chitin treatment at the protein level, predominantly through myeloid cell reduction, a selected set of 68 and 48 inflammation-related genes were downregulated in chitin- and chitin + anti-PD-1-treated primary tumors of respectively the 4T1- and the 66cl4-based model. Importantly, genes that have been associated with the signaling and pro-tumorigenic activity of a prominent CLP family member, i.e. CHI3L1, were also downregulated in primary tumors following chitin treatment either with or without anti-PD-1, including Usf1 and Rab37 in the 4T1-based model and Lgals3 in the 66cl4-based model. Conclusion: Our findings highlight that chitin, as a general CLP blocker, reduces cancer-associated immunosuppression and enhances anti-tumor immunity as well as ICB responses in complementary ICB-resistant TNBC models, supporting its potential clinical relevance in immunosuppressed TNBC patients.
2024-02-25 | GSE256439 | GEO
Project description:Epithelial injury underlies fibrotic and inflammatory lung diseases during which regenerative responses become dysregulated or recurrently engaged. Although environmental exposures are risk factors for severe lung disease, specific drivers of persistent epithelial and immune dysfunction are poorly understood. Here we identify a feedback circuit triggered by chitin, a common component of airborne particulate matter, that impacts lung health and regeneration after epithelial injury. In mice, damage to epithelial cells results in loss of homeostatic lung chitinase activity and accumulation of environmental chitin substrates; these disturbances impair epithelial renewal and drive activation of group 2 innate lymphoid cells (ILC2s). ILC2s, in turn, restore chitinase activity by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells, thereby promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear airway chitin and exhibit exacerbated inflammation, impaired epithelial regeneration, and increased mortality following epithelial injury. These effects are ameliorated by chitinase replacement therapy or AMCase overexpression, demonstrating that chitin degradation is crucial for restoring lung homeostasis after perturbation. The ILC2-chitinase response circuit thus comprises a tissue adaptation to a widespread environmental constituent and may be a target for alleviating persistent post-injury lung epithelial and immune dysfunction.
2024-12-31 | GSE275319 | GEO
Project description:Epithelial injury underlies fibrotic and inflammatory lung diseases during which regenerative responses become dysregulated or recurrently engaged. Although environmental exposures are risk factors for severe lung disease, specific drivers of persistent epithelial and immune dysfunction are poorly understood. Here we identify a feedback circuit triggered by chitin, a common component of airborne particulate matter, that impacts lung health and regeneration after epithelial injury. In mice, damage to epithelial cells results in loss of homeostatic lung chitinase activity and accumulation of environmental chitin substrates; these disturbances impair epithelial renewal and drive activation of group 2 innate lymphoid cells (ILC2s). ILC2s, in turn, restore chitinase activity by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells, thereby promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear airway chitin and exhibit exacerbated inflammation, impaired epithelial regeneration, and increased mortality following epithelial injury. These effects are ameliorated by chitinase replacement therapy or AMCase overexpression, demonstrating that chitin degradation is crucial for restoring lung homeostasis after perturbation. The ILC2-chitinase response circuit thus comprises a tissue adaptation to a widespread environmental constituent and may be a target for alleviating persistent post-injury lung epithelial and immune dysfunction.
2024-12-31 | GSE275075 | GEO
Project description:Epithelial regeneration is modulated by chitin and chitinase activity
| PRJNA1150251 | ENA
Project description:Epithelial regeneration is modulated by chitin and chitinase activity
| PRJNA1149062 | ENA
Project description:BackgroundChitinase-like proteins (CLPs) play a key role in immunosuppression under inflammatory conditions such as cancer. CLPs are enzymatically inactive and become neutralized upon binding of their natural ligand chitin, potentially reducing CLP-driven immunosuppression. We investigated the efficacy of chitin treatment in the context of triple-negative breast cancer (TNBC) using complementary mouse models. We also evaluated the immunomodulatory influence of chitin on immune checkpoint blockade (ICB) and compared its efficacy as general CLP blocker with blockade of a single CLP, i.e. chitinase 3-like 1 (CHI3L1).MethodsFemale BALB/c mice were intraductally injected with luciferase-expressing 4T1 or 66cl4 cells and systemically treated with chitin in combination with or without anti-programmed death (PD)-1 ICB. For single CLP blockade, tumor-bearing mice were treated with anti-CHI3L1 antibodies. Metastatic progression was monitored through bioluminescence imaging. Immune cell changes in primary tumors and lymphoid organs (i.e. axillary lymph nodes and spleen) were investigated through flow cytometry, immunohistochemistry, cytokine profiling and RNA-sequencing. CHI3L1-stimulated RAW264.7 macrophages were subjected to 2D lymphatic endothelial cell adhesion and 3D lymphatic integration in vitro assays for studying macrophage-mediated lymphatic remodeling.ResultsChitin significantly reduced primary tumor progression in the 4T1-based model by decreasing the high production of CLPs that originate from tumor-associated neutrophils (TANs) and Stat3 signaling, prominently affecting the CHI3L1 and CHI3L3 primary tumor levels. It reduced immunosuppressive cell types and increased anti-tumorigenic T-cells in primary tumors as well as axillary lymph nodes. Chitin also significantly reduced CHI3L3 primary tumor levels and immunosuppression in the 66cl4-based model. Compared to anti-CHI3L1, chitin enhanced primary tumor growth reduction and anti-tumorigenicity. Both treatments equally inhibited lymphatic adhesion and integration of macrophages, thereby hampering lymphatic tumor cell spreading. Upon ICB combination therapy, chitin alleviated anti-PD-1 resistance in both TNBC models, providing a significant add-on reduction in primary tumor and lung metastatic growth compared to chitin monotherapy. These add-on effects occurred through additional increase in CD8α+ T-cell infiltration and activation in primary tumor and lymphoid organs.ConclusionsChitin, as a general CLP blocker, reduces CLP production, enhances anti-tumor immunity as well as ICB responses, supporting its potential clinical relevance in immunosuppressed TNBC patients.
| S-EPMC11007917 | biostudies-literature
Project description:The marine bacterium Aliivibriosalmonicida (formerly Vibrio salmonicida) is the causative agent of cold water vibriosis, a disease that led to severe losses in Norwegian aquaculture during the 1980s. Genes encoding a glycoside hydrolase family 18 (GH18) chitinase and two lytic polysaccharide monooxygenases (LPMOs) containing chitin binding domains are encoded in the genome of this bacterium, indicating a chitin degrading capability. However, due to extensive gene decay, some parts of the chitinolytic pathways are believed to be dysfunctional. To investigate the chitinolytic abilities of the bacterium, we combined microbiological and biochemical experiments with proteomic analysis. The family GH18 chitinase was able to depolymerize - and -chitin, but its activity was up to 50-fold lower compared to other well-studied chitinases from Serratia marcescens and Cellvibrio japonicus. The two LPMOs showed activity on chitin, cleaving the substrate chains by oxidation. Cultivation experiments showed that Al. salmonicida was able to grow on and utilize the soluble building blocks of chitin; N-acetyl-D-glucosamine (GlcNAc) and chitobiose (GlcNAc2). Furthermore, cultivation and gene deletion studies revealed that the bacterium was able to degrade insoluble chitin, albeit at a slow rate, and that growth on this substrate was dependent on the GH18 chitinase, but to a lesser extent the LPMOs. Finally, expression of the GH18 chitinase and both LPMOs was detected by proteomic analysis of Al. salmonicida cultivated on chitin as the sole carbon source. In conclusion, our results show that Al. salmonicida LFI1238 can utilize chitin as source of nutrients and its ability depends on the GH18 chitinase.
2021-07-26 | PXD021397 | Pride
Project description:Chitinases are ubiquitous enzymes involved in biomass degradation and chitin turnover in nature. Pseudomonas aeruginosa (PA), an opportunistic human pathogen, expresses ChiC, a secreted glycoside hydrolase 18 (GH18) family chitinase. Despite speculation about ChiC's role in PA disease pathogenesis, there is scant evidence supporting this hypothesis. Since PA cannot catabolize chitin, we investigated the potential function(s) of ChiC in PA pathophysiology
2024-04-30 | PXD048596 | Pride
Project description:Chitinases are ubiquitous enzymes involved in biomass degradation and chitin turnover in nature. Pseudomonas aeruginosa (PA), an opportunistic human pathogen, expresses ChiC, a secreted glycoside hydrolase 18 (GH18) family chitinase. Despite speculation about ChiC's role in PA disease pathogenesis, there is scant evidence supporting this hypothesis. Since PA cannot catabolize chitin, we investigated the potential function(s) of ChiC in PA pathophysiology
2024-04-30 | PXD048320 | Pride
Project description:Genome mining of pigmented Pseudoalteromonas has revealed a large potential for production of bioactive compounds, both hydrolytic enzymes and secondary metabolites and the purpose of the present study was to explore this bioactivity potential in a potent antibiotic and enzyme producer, Pseudoalteromonas rubra strain S4059. Proteomic analyses indicated that a highly efficient chitin degradation machinery was present in the red-pigmented P. rubra S4059 when grown on chitin. Four GH18 chitinases and two GH20 hexosaminidases were significantly upregulated by chitin. GH19 chitinase which is not common in bacteria is consistently found in pigmented Pseudoalteromonas and in S4059 it was only detected when the bacterium was grown on chitin. To explore the possible role of GH19 in pigmented Pseudoalteromonas, we deleted the GH19 chitinase and compared a range of phenotypes in the mutant and wild type. Neither, the chitin degrading ability or the biofilm forming capacity was affected by GH19 deletion. In some Vibrionaceae, the secondary metabolome is significantly affected by growth on chitin as compared to simpler carbon sources. The secondary metabolites produced by S4059 and the GH19 mutant were xxx start by chitin/mannose – then the mutant. not altered by the absence of the gene, indicating that chitin utilization may not directly influence the production of secondary metabolites as has been observed in some Vibrionaceae. Metabolome analysis reveal that growth on chitin XX. In summary,
2021-03-11 | PXD023249 | Pride