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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Immune response biomarker profiling of serum from prostate cancer patients treated with anti-CTLA-4 immunotherapy.

ABSTRACT: Anti-CTLA-4 induced antibody responses to antigens in prostate cancer patients. Pre-treatment and post-treatment sera from 5 clinical responders and 6 clinical non-responders were used to hybridize protein arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Serena Kwek

PROVIDER: E-GEOD-39688 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients.

Kwek Serena S SS Dao Vinh V Roy Ritu R Hou Yafei Y Alajajian David D Simko Jeffrey P JP Small Eric J EJ Fong Lawrence L

Journal of immunology (Baltimore, Md. : 1950) 20120905 7

CTLA-4 is a surface receptor on activated T cells that delivers an inhibitory signal, serving as an immune checkpoint. Treatment with anti-CTLA-4 Abs can induce clinical responses to different malignancies, but the nature of the induced Ag-specific recognition is largely unknown. Using microarrays spotted with >8000 human proteins, we assessed the diversity of Ab responses modulated by treatment with CTLA-4 blockade and GM-CSF. We find that advanced prostate cancer patients who clinically respon ...[more]

PMID: 22956585

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Gene expression patterns in responding versus non-responding AB1-HA tumors from mice during immunotherapy

Project description:Balb/c mice were inoculated subcutaneously with AB1-HA cells on both flanks on day 0. The mice were then treated with anti-CTLA-4 on day 5 or 6. 7 days later, one tumor was removed for gene expression studies, and the other was left in situ to monitor tumor growth and determine if the eventual outcome was progression or regression. The study design consisted of three experimental groups; (i) untreated mice; (ii) anti-CTLA-4 treated responders; (iii) anti-CTLA-4 treated nonresponders. There were 10 animals in each group.

2015-07-22 | E-GEOD-63557 | biostudies-arrayexpress

Immune response biomarker profiling of serum from prostate cancer patients treated with anti-CTLA-4 immunotherapy.

Project description:Anti-CTLA-4 induced antibody responses to antigens in prostate cancer patients.

2012-11-05 | GSE39688 | GEO

RNAseq of tumor samples from CT26 syngeneic mouse treated with a PD-L1 and CTLA-4 immunotherapy combination

Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.

2020-04-16 | E-MTAB-7777 | biostudies-arrayexpress

Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies

Project description:Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance since mice expressing the VH and VL regions of 2F5 have a block in B-cell development characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. Here we identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes a conformational epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but retain all SF3B3 4E10 epitopes. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motif shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1. The invitrogen protoarray that contains >9,400 recombinant human proteins was used to identify self-ligands that are recognized by broadly neutralizing HIV-1 antibodies 2F5 and 4E10. An isotype-matched human myeloma protein (151K, Southern Biotech) was used as control.

2012-12-03 | E-GEOD-42673 | biostudies-arrayexpress

In vivo gene expression data from wild type and CTLA-4 KO 5C.C7 T cells

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2012-09-05 | E-GEOD-37563 | biostudies-arrayexpress

Artificial Intelligence-powered Drug Discovery against CTLA-4 in Cancer

Project description:Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with B7 proteins CD80 and CD86. CTLA-4 is the first immune checkpoint targeted with a monoclonal antibody inhibitor. Checkpoint inhibitors have generated durable responses in many cancer patients, representing a revolutionary milestone in cancer immunotherapy. However, therapeutic efficacy is limited to a small portion of patients, and immune-related adverse events are noteworthy, especially for monoclonal antibodies directed against CTLA-4. Previously, small molecules have been developed to impair the CTLA-4: CD80 interaction; however, they directly targeted CD80 and not CTLA-4. In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to target CTLA-4. We validated primary hits with biochemical, biophysical, immunological, and experimental animal assays. We then optimized lead compounds and obtained inhibitors with an inhibitory concentration of 1 micromole in disrupting the interaction between CTLA-4 and CD80. Unlike ipilimumab, these small molecules did not degrade CTLA-4. Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. This project supports an AI-based framework in designing small molecules targeting immune checkpoints for cancer therapy.

2024-02-15 | GSE228560 | GEO

Autoantibody profiling of sera from individuals with Systemic Lupus Erythematosus (SLE) by protein microarray

Project description:We developed a protein microarray to identify autoantigens in Systemic Lupus Erythematosus (SLE). Baculovirus-Sf9 cell expression system was used to create a protein microarray with 1543 full-length human proteins expressed with a biotin carboxyl carrier protein (BCCP) folding tag. We assayed sera from UK and USA SLE individuals (total n=277), age/ancestry matched control cohorts (n=280) and a confounding disease cohort (n=92).

2018-03-01 | E-MTAB-5900 | biostudies-arrayexpress

CTLA-4 pathway is instrumental in Giant Cell Arteritis

Project description:BACKGROUND: Giant Cell Arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T cells infiltration. The roles that immune checkpoints play in pathogenesis of GCA are still unclear.Our aim was to study the immune checkpoints interplay in GCA. METHODS: First, we used VigiBase, the WHO international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors (ICI) treatments. We then further dissected the role of ICI in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics and flow cytometry on peripheral blood mononuclear cells (PBMCs) and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune related adverse event associated with anti-CTLA-4 (Cytotoxic T-lymphocyte-associated-protein-4) but not anti-PD-1/PD-L1 treatment. We further dissected a critical role for CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4+ T cells (and specifically Tregs) present in blood and aorta of GCA patients versus controls. While Tregs were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4+ Ki-67+ Tregs from GCA were more sensitive to anti-CTLA-4 (Ipilimumab)-mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA which provides a strong rationale for targeting this pathway.

2023-07-03 | GSE236367 | GEO

Gene Expression Profiling of human monocytes: Combination Therapy with AntiâCTLA-4 and AntiâPD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood monocytes Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) and functional signatures in vivo in purified human T cells and monocytes. RNA extracted from freshly isolated monocytes from peripheral blood of patients treated with either antiâPD-1 (n = 6), antiâCTLA-4 (n = 5), Combo therapy with antiâPD-1 and antiâCTLA-4 concurrently (Combo, n = 6), and Seq antiâPD-1 in patients with prior antiâCTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-16 | E-GEOD-77924 | biostudies-arrayexpress

Gene Expression Profiling of human T cells: Combination Therapy with Antiâ??CTLA-4 and Antiâ??PD-1 Leads to Distinct Immunologic Changes In Vivo

Project description:Transcriptome analysis of human peripheral blood T cells Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic (changes in gene-expression profile) andfunctional signatures in vivo in purified human T cells. RNA extracted from freshly isolated T cells from peripheral blood of patients treated with either antiâ??PD-1 (n = 6), antiâ??CTLA-4 (n = 5), Combo therapy with antiâ??PD-1 and antiâ??CTLA-4 concurrently (Combo, n = 6), and Seq antiâ??PD-1 in patients with prior antiâ??CTLA-4 (Seq, n = 3) was analyzed using the Affymetrix GeneChip Human Transcriptome 2.0 exon array. No techinical replicates were performed.

2016-02-10 | E-GEOD-77714 | biostudies-arrayexpress

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