PD-1/PD-L1 immune checkpoint and p53 loss facilitate tumor progression in activated B cell diffuse large B-cell lymphomas
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA478047 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-04-19 | GSE116290 | GEO
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:Cellular quiescence is a reversible and tightly regulated stem cell function that is essential for healthy aging. However, the control elements of tissue-specific renewal, quiescence, and aging remain poorly understood. Using melanocyte stem cells (McSCs) to model and test the regulation of tissue-specific quiescence, we find that stem cell quiescence is neither a singular nor static process. McSCs display remarkable heterogeneity, with a fraction expressing the immune checkpoint protein PD-L1. Differential gene expression profiling identifies tissue-specific control of this immune privilege, specifically during melanocyte stem cell dormancy. In vitro quiescence assays confirm that inducing quiescence is sufficient to drive PD-L1 expression in melanoblasts and PD-L1 subsequently regulates aspects of melanoblast cell cycling. In vivo, a portion of McSCs appear to leverage this immune checkpoint as a key aspect of their dynamics during the dormant stage of the hair cycle. With age, this dynamic becomes unbalanced, tipping towards a higher proportion of PD-L1-expressing McSCs and a more deeply quiescent McSC pool. Collectively, these findings demonstrate that immune checkpoint expression is a physiological attribute of McSC quiescence and offer PD-L1-expressing quiescent stem cells as molecular targets for potential reactivation in regenerative and gerontological medicine.
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Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
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Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
2017-02-01 | GSE94130 | GEO
Project description:BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-γ induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274.
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Project description:Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (N=246) resulted in 3 separate DLBCL groups partly overlapping with GCB versus ABC like phenotype. One group with poor clinical outcome was characterized by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A 2nd group, also with poor clinical outcome, was characterized by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The 3rd group showing a favourable outcome was characterized by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterized either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralizing the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL. Keywords: expression profiling B lymphomas
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