DRG2 is required for cell surface localization of PD-L1 in melanoma cells and optimum response to anti-PD-1 immune checkpoint blockade [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA970346 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24471408.fastq.gz | Fastqsanger.gz | |||
| SRR24471409.fastq.gz | Fastqsanger.gz | |||
| SRR24471410.fastq.gz | Fastqsanger.gz | |||
| SRR24471411.fastq.gz | Fastqsanger.gz |
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Project description:DRG2 is required for cell surface localization of PD-L1 in melanoma cells and optimum response to anti-PD-1 immune checkpoint blockade
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Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
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Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
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Project description:DRG2 is required for cell surface localization of PD-L1 in melanoma cells and optimum response to anti-PD-1 immune checkpoint blockade [bulk RNA-seq]
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Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
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Project description:Alzheimer’s disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a PD-1 ligand, was found to have similar efficacy to that of PD-1 blocking in disease modification, in both animal models of AD and of tauopathy. Targeting PD-L1 in a tau-driven disease model resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma. Single cell RNA-seq revealed that the homing macrophages expressed unique scavenger molecules including macrophage scavenger receptor 1 (MSR1), which was shown here to be required for the effect of PD-L1 blockade in disease modification. Overall, our results demonstrate that immune checkpoint blockade targeting the PD-1/PD-L1 pathway leads to modification of common factors that go awry in AD and dementia, and thus can potentially provide an immunotherapy to help combat these diseases.
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Project description:Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS
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Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
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Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
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Project description:PD-L1 Inhibitor Regulates the miR-33a-5p/PTEN Signaling Pathway and Can Be Targeted to Sensitize Glioblastomas to Radiation. Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Ionizing radiation (IR) is a standard treatment for GBM patients and results in DNA damage. However, the clinical efficacy of IR is limited due to therapeutic resistance. The programmed death ligand 1 (PD-L1) blockade has a shown the potential to increase the efficacy of radiotherapy by inhibiting DNA damage and repair responses. The miR-33a-5p is an essential microRNA that promotes GBM growth and self-renewal. In this study, we investigated whether a PD-L1 inhibitor (a small molecule inhibitor) exerted radio-sensitive effects to impart an anti-tumor function in GBM cells by modulating miR-33a-5p. U87 MG cells and U251 cells were pretreated with PD-L1 inhibitor. The PD-L1 inhibitor-induced radio-sensitivity in these cells was assessed by assaying cellular apoptosis, clonogenic survival assays, and migration. TargetScan and luciferase assay showed that miR-33a-5p targeted the phosphatase and tensin homolog (PTEN) 3' untranslated region. The expression level of PTEN was measured by western blotting, and was also silenced using small interfering RNAs. The levels of DNA damage following radiation was measured by the presence of γ-H2AX foci, cell cycle, and the mRNA of the DNA damage-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated that the PD-L1 inhibitor significantly decreased the expression of the target gene, miR-33a-5p. In addition, pretreatment of U87 MG and U251 cells with the PD-L1 inhibitor increased radio-sensitivity, as indicated by increased apoptosis, while decreased survival and migration of GBM cells. Mir-33a-5p overexpression or silencing PTEN in U87 MG and U251 cells significantly attenuated PD-L1 radiosensitive effect. Additionally, PD-L1 inhibitor treatment suppressed the expression of the DNA damage response-related genes, BRCA1, NBS1, RAD50, and MRE11. Our results demonstrated a novel role for the PD-L1 inhibitor in inducing radio- sensitivity in GBM cells, where inhibiting miR-33a-5p, leading to PTEN activated, and inducing DNA damage was crucial for antitumor immunotherapies to treat GBM.
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