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SRP077574
Mus musculus
29 Downloadable Samples
Illumina HiSeq 2000
Description
The goal of this study is to investigate if interferon signaling regulates immune checkpoint blockade in mouse melanoma model. Overall design: Transcription profiling for B16, B16 after chronic interferon treatment, B16 derived checkpoint blockade resistant strain 499 and various knockout from 499, coupled with ATA-seq data.
Publication Title
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 14 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Response to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.
Publication Title
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 14 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Targeting components of the mitogen-activated protein kinase (MAPK) pathway prolongs survival of patients with advanced BRAFV600E melanomas but such an approach is not curative because of the rapid acquisition of numerous resistance mechanisms. Here we analyze melanoma cells that evade MAPK inhibitors by undergoing a senescence-like, slow-growth, phenotype, which leads to acquired resistance. The initial therapeutic response is characterized by an integrated stress response program, including stimulation of autophagic flux, activation of the endoplasmic reticulum machinery, and an enhanced ability of detoxifying reactive oxygen species. Reversibly senescent cells also exhibit an increase in mitochondrial genome copy number and a strong metabolic shift towards oxidative phosphorylation (OxPhos). Inducing mitochondrial dysfunction by co-targeting the MAPK pathway and mitochondrial Hsp90-directed protein folding with specific inhibitors prevented entry of cells into a reversibly senescent state, suppressed mitochondrial energy metabolism and augmented therapy response.
Publication Title
Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.
Sample Metadata Fields
Disease, Disease stage, Cell line, Time
View Samples- Mus musculus
- 22 Downloadable Samples
- Illumina HiSeq 4000
Description
CD47 is a ubiquitous cell surface receptor that limits cell clearance by phagocytes that express its counter-receptor signal-regulatory protein-a and directly regulates T cell immunity by interacting with its inhibitory ligand thrombospondin-1. Murine natural killer (NK) cells express higher levels of CD47 than other lymphocytes, but the role of CD47 in regulating NK cell homeostasis and immune function remains unclear. Cd47-/- mice exhibited depletion of NK precursors in bone marrow, but antisense Cd47 knockdown or gene disruption resulted in a dose dependent accumulation of immature and mature NK cells in spleen. Cd47-/- mice were impaired in controlling chronic Clone-13 lymphocytic choriomeningitis virus (LCMV) infection, which was associated with depletion of splenic NK cells and loss of effector cytokine and interferon response gene expression in Cd47-/- NK cells. These data identify CD47 as a cell-intrinsic and systemic regulator of NK cell homeostasis and NK cell responses to viral infection. Overall design: Examining natural killer (NK) cell intrinsic role of CD47 during viral infection.
Publication Title
CD47 Expression in Natural Killer Cells Regulates Homeostasis and Modulates Immune Response to Lymphocytic Choriomeningitis Virus.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 3000
Description
Sustained spermatogenesis in adult males and recovery of fertility following germ cell depletion are dependent on undifferentiated spermatogonia with self-renewal potential. We have previously demonstrated a critical cell-autonomous role for Gilz in spermatogonial stem cell maintainance and spermatogenesis. To identify genes regulated by Gilz in the male germline, we have isolated undifferentiated spermatogonial cells from tamoxifen treated Gilzflox/flox (Control) and Gilzflox/flox UBC-CreER (TAM-KO) mice that will allow identification of genes mis-expressed upon loss of GILZ. Overall design: 4 independent sets of Gilzflox/flox (Control) and Gilzflox/flox UBC-CreER (TAM-KO) undifferentiated spermatogonia were isolated by flow sorting from adult mouse testes 7 days after treatment with tamoxifen.
Publication Title
GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarray to look at the genes deregulated in PaTu8988s (adenovirus insensitive) and PaTu8988t (adenovirus sensitive) cell lines
Publication Title
CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2500
Description
Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute and chronic infectious diseases remains unclear. We recently demonstrated that IFN-??? receptor (IFNAR) signaling promotes Treg function in autoimmunity. To dissect the functional role of IFNAR-signaling in Tregs during acute and chronic viral infection, we infected Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice with LCMV Armstrong and Clone-13. In both models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced expression of Treg associated activation antigens. The enhanced activated phenotype was also seen when we compared the transcriptomes of IFNARfl/flxFoxp3YFP-Cre and wild type (WT) Tregs by RNA-Seq on day 25-post Clone-13 infection. LCMV-specific CD8+ T cells from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral IFN? and TNF? in both acute and chronic LCMV. In the chronic model, the numbers of anti-viral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs than WT mice during chronic infection. Thus, type I IFN signaling in Tregs is context-dependent, resulting in enhanced suppressor function in some models of autoimmunity, but decreased suppressor function in acute and chronic viral infection. Overall design: mRNA from Treg cells from 5 WT and 5 IFNAR deficient mice were analyzied by RNA-seq using Illumina HiSeq
Publication Title
Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Pericytes derived from skin dermis can substantially enhance the short-term tissue-regenerative capacity of human epidermal cells already committed to differentiation; they also display both phenotypic and functional properties of mesenchymal stem cells. In this microarray analysis, we compared the gene expression profile of dermal pericytes to that of the remaining dermal cells of neonatal human foreskin.
Publication Title
A role for pericytes as microenvironmental regulators of human skin tissue regeneration.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
The conditioned media from Bifidobacterium infantis (BCM) and Lactobacillus acidophilus (LCM) were reported to promote maturation of innate immune response gene expression, which explained the protective effects of probiotics in clinical necrotizing enterocolitis. We used microarray analysis to investigate the expression of genes involved in regulation of BCM and LCM in IL-1 stimulated immature human enterocytes.
Publication Title
Secreted Metabolites of Bifidobacterium infantis and Lactobacillus acidophilus Protect Immature Human Enterocytes from IL-1β-Induced Inflammation: A Transcription Profiling Analysis.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Acute myeloid leukemia (AML) is driven by somatic mutations and genomic rearrangements affecting >20 genes. Many of these are recent discoveries and how this molecular heterogeneity dictates AML pathophysiology and clinical outcome remains unclear. Methods: We sequenced 111 leukemia genes for driver mutations in 1540 AML patients with cytogenetic and clinical data. We modeled AMLs genomic structure, defining genetic interactions, patterns of temporal evolution and clinical correlations. Results: We identified 5,236 driver mutations involving 77 loci, including hotspot mutations in MYC. We found 1 driver mutation in 96% patients, and 2 in 85%. Gene mutations implicated in age related clonal hematopoiesis (DNMT3A, ASXL1, TET2) were the earliest in AML evolution, followed by highly specific and ordered patterns of co-mutation in chromatin, transcription and splicing regulators, NPM1 and signaling genes. The patterns of co-mutation compartmentalize AML into 12 discrete molecular classes, each presenting with distinct clinical manifestation. Amongst these, mutations in chromatin and spliceosome genes demarcate a molecularly heterogeneous subgroup enriched for older AML patients currently classified as intermediate risk and results in adverse prognosis. Two- and three-way genetic interactions often implicating rare genes/mutation-hotspots, markedly redefined clinical response and long-term curability, with the NPM1:DNMT3A:FLT3ITD genotype (6% patients) identifying poor prognosis disease, whereas within the same class NPM1:DNMT3A:NRASG12/13 (3%) associated with favorable outlooks. Conclusions: 79% of AML is molecularly classified in 12 genomic subgroups. These represent distinct molecular phylogenies, implicating complex genotypes. Delineation of higher-order genomic relationships, guide the development of personally tailored classification, prognostication and clinical protocols. Similar studies across cancer types are warranted.
Publication Title
Genomic Classification and Prognosis in Acute Myeloid Leukemia.
Sample Metadata Fields
Specimen part, Disease
View Samples