Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD004420
PROVIDER: PRJNA326271 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3703360.fastq.gz | Fastqsanger.gz | |||
| SRR3703370.fastq.gz | Fastqsanger.gz | |||
| SRR3703361.fastq.gz | Fastqsanger.gz | |||
| SRR3703371.fastq.gz | Fastqsanger.gz | |||
| SRR3703362.fastq.gz | Fastqsanger.gz |
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Project description:In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell–derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)–deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.
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Project description:Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
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Project description:Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors in circulation. Their interactions with myeloid cells could lead to the generation of myeloid-derived suppressor cells (MDSC), which strongly inhibit the anti-tumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced such immunosuppressive activity via upregulating the expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90a (HSP90a) in EV and on the toll-like receptor (TLR) on myeloid cells. Here, we investigated whether soluble HSP90α could convert monocytes into immunosuppressive MDSC. CD14+ monocytes were isolated from the peripheral blood of healthy donors, incubated with human rHSP90α alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess immunosuppressive function of rHSP90α-treated monocytes. The concentration of HSP90α was measured by ELISA in plasma of advanced melanoma patients and correlated with clinical outcome. We found that the incubation of monocytes with rHSP90α for 16 h resulted in a strong upregulation of PD-L1 expression, whereas ROS and NO production as well as the expression of arginase-1, adenosine producing ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation can be blocked by anti-TLR4 antibodies and an NF-κB inhibitor. After longer incubation (for 24h), rHSP90α-treated monocytes downregulated HLA-DR expression and acquired an augmented viability and resistance to apoptosis. Moreover, these monocytes were converted into MDSC indicated by their capacity to inhibit T cell proliferation mediated by TLR4 signaling as well as PD-L1 and indolamin-2,3-Dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of melanoma patients correlated with augmented PD-L1 expression on circulating monocytic (M) MDSC. Furthermore, melanoma patients with high levels of HSP90α displayed shorter progression-free survival (PSF) upon the treatment with immune checkpoint inhibitors (ICI).
2022-06-29 | GSE207075 | GEO
Project description:Tumor-derived small extracellular vesicles (TEVs) were reported to carry various immunosuppressive molecules regulating immune response. We previously reported that TEV could express PD-L1 to systematically inhibit CD8 T cell anti-tumor immunity. Here, we observed that TEV PD-L1 suppressed the phagocytosis and bactericidal capacity of macrophages against E. coli. To investigate the potential mechanisms behind the impaired phagocytosis further, we collected and purified exosomes from the melanoma cell line B16-F10 PD-L1 knockout (KO) or vector culture to challenge RAW264.7 cells. We used RNA sequencing to reveal the key functional associated molecules for inhibiting the phagocytosis-associated pathway.
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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
Project description:Primary outcome(s): Correlation between PD-L1 expression in immune cells and soluble PD-L1 value. Correlation between PD-L1 expression in immune cells or soluble PD-L1 value and PD-L1 expression in tumor tissue. Characterstics of PD-L1 expression in immune cells or soluble PD-L1 value in each gastrointestinal cancer type.
| 2638777 | ecrin-mdr-crc
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.
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Project description:ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma
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Project description:ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma
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Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
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