Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1234857 | ENA |
REPOSITORIES: ENA
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Project description:Bulk RNA sequencing was performed to investigate transcriptomic changes in 4T1 tumors treated with anti-PD-L1 therapy. Tumors were derived from 4T1 control and PD-L1-overexpressing cells injected into mice, followed by IgG or anti-PD-L1 treatment. Gene expression analysis revealed distinct immune-related pathway alterations, with reduced immune activation in PD-L1-overexpressing tumors. Differentially expressed genes suggested an immunosuppressive tumor microenvironment, potentially contributing to resistance to anti-PD-L1 therapy. These findings provide insights into the molecular mechanisms underlying immune checkpoint inhibitor response in triple-negative breast cancer.
2025-03-28 | GSE292013 | GEO
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:We determined the immune cell composition and their gene expression, by performing single-cell RNA sequencing (scRNA-seq), in anti-PD-L1-treated 2F8cis tumors, a hot and immunoresponsive ovarian murine tumor model, and anti-PD-L1-treated 2F8cis/CA-MSC tumors. We also evaluated the ability of hedgehog inhibitor (HHi) therapy to reverse CA-MSC effects. Adipose-derived mesenchymal stem cells (MSC) were cultured with 2F8cis, an ovarian mouse tumor cell line, to generate cancer-associated MSC (CA-MSC). 2F8cis tumor cell alone or 2F8cis/CA-MSCs co-cultured cells at ratio 1:1 were injected into C57BL/6J mice. Tumor infiltrating CD45+ cells were isolated from anti-PD-L1-treated 2F8cis (Group 1, n=3), anti-PD-L1-treated 2F8cis/CA-MSCs (Group 2, n=3), anti-PD-L1+ IPI-926-treated 2F8cis/CA-MSCs (Group 3, n=3) tumors. Samples were labeled with different TotalSeq oligo-conjugated antibodies and loaded into the Chromium instrument (10x Genomics). The resulting barcoded cDNAs were used to construct libraries. Single-cell cDNA libraries were then processed for RNA sequencing using an Illumina NextSeq-500 platform. Anti-PD-L1-treated 2F8cis/CA-MSC tumors showed a high number of Monocytes and macrophages over-expressing Ccr2 and Tgfbi when compared to anti-PD-L1 responsive 2F8cis tumors. Our results also indicated that IPI-926 restored response to anti-PD-L1 therapy decresing the expression of Ccr2 and Tgfbi both in monocytes and macrophages. Our study represents the first detailed analysis generated by RNA-seq technology of 2F8cis/CA-MSC+ enriched tumor transcriptomes, treated with anti-PDL1 alone or in combination with HHi, and compared with anti-PDL1-treated tumors. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles.
2021-10-06 | GSE185013 | GEO
Project description:B cells potentially play a role in the immune response to melanoma, including during treatment with immune modulators. We profiled (transcriptome analysis) effects of anti-PD-L1 antibody therapy on gene expression in B16 melanoma tumors of B cells depleted and WT syngeneic mice. After 7 days of B16 tumors implantation, mice were treated or untreated with anti-PD-L1 antibody (every three days).
2022-05-15 | GSE202879 | GEO
Project description:Programmed death-ligand 1, PD-L1 (CD274), is expressed by cancer cells to facilitate immune evasion. PD-L1 also exerts pro-survival functions in cancer cells, and mechanisms that regulate intracellular PD-L1 signaling remain largely unknown. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF-b-receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), which are highly resistant to immunotherapy. Mechanistically, we show here that internalized PD-L1, mediated by its cytoplasmic domain, including the S278/S279 residues, in response to CerS4/C18/C20-ceramide downregulation or genetic loss, interacts with an RNA-binding protein Caprin-1 in various metastatic breast cancer models, including 4T1 orthotopic breast allografts and mammary tumors developed in MMTV-PyMT/CerS4-/- compared to MMTV-PyMT/CerS4+/+ mice, consistent with Shh/TGFBR1/Wnt/b-catenin activation in-vivo. Genetic loss or molecular knockdown of CerS4 in breast tumors also resulted in increased infiltration of FoxP3+ T regs that are known to suppress anti-tumor immunity. Targeting the CerS4/Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody in mice containing metastatic breast tumors in which CerS4 is downregulated vastly decreased tumor growth and metastasis, leading to inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and multiple patient datasets, demonstrate a mechanism to define intracellular metastatic signaling by PD-L1 internalization in response to alterations of ceramide metabolism, providing a new therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
2024-07-07 | GSE250638 | GEO
Project description:Programmed death-ligand 1, PD-L1 (CD274), is expressed by cancer cells to facilitate immune evasion. PD-L1 also exerts pro-survival functions in cancer cells, and mechanisms that regulate intracellular PD-L1 signaling remain largely unknown. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF-b-receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), which are highly resistant to immunotherapy. Mechanistically, we show here that internalized PD-L1, mediated by its cytoplasmic domain, including the S278/S279 residues, in response to CerS4/C18/C20-ceramide downregulation or genetic loss, interacts with an RNA-binding protein Caprin-1 in various metastatic breast cancer models, including 4T1 orthotopic breast allografts and mammary tumors developed in MMTV-PyMT/CerS4-/- compared to MMTV-PyMT/CerS4+/+ mice, consistent with Shh/TGFBR1/Wnt/b-catenin activation in-vivo. Genetic loss or molecular knockdown of CerS4 in breast tumors also resulted in increased infiltration of FoxP3+ T regs that are known to suppress anti-tumor immunity. Targeting the CerS4/Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody in mice containing metastatic breast tumors in which CerS4 is downregulated vastly decreased tumor growth and metastasis, leading to inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and multiple patient datasets, demonstrate a mechanism to define intracellular metastatic signaling by PD-L1 internalization in response to alterations of ceramide metabolism, providing a new therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
2024-07-07 | GSE250637 | GEO
Project description:Macrophage phenotype in anti-PD-L1 treated MC38 tumors
| PRJNA516065 | ENA
Project description:EB-FAPI or EB-FAPI+anti-PD-L1 antibody combination treated tumor mice raw sequence reads
| PRJNA983537 | ENA
Project description:Primary irradiated MC38 tumors and secondary MC38 non-irradiated tumors. Subcutaneous MC38 tumors in C57BL/6 mice Concurrent treatment with anti-PD-L1.
2023-10-15 | E-MTAB-13389 | biostudies-arrayexpress