A novel nanobody-based TCR-like CAR-T therapy targeting PRAME for the treatment of acute myeloid leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE320438 | GEO | 2026/04/25
REPOSITORIES: GEO
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Project description:Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.
2023-03-10 | PXD040651 | Pride
Project description:Abstract BACKGROUND: Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers. OBJECTIVES: The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology. METHODS: We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles. RESULTS: PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis. CONCLUSIONS: The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.
2009-05-31 | GSE8079 | GEO
Project description:Preferentially Expressed Antigen of Melanoma (PRAME) is a cancer-testis antigen that is expressed in subsets of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), collectively termed keratinocyte carcinomas (KC). PRAME functions as a transcriptional co-repressor of retinoid signaling by guiding enhancer of zeste homologue 2 (EZH2), a repressive histone methyltransferase, to retinoic acid response elements (RARE) found in gene promoters. The functions and therapeutic relevance of PRAME expression in KC have not been investigated. In the present study, we evaluated the implications of PRAME expression upon KC development and response to retinoid-based therapeutics. High PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. Similarly, PRAME overexpression (OE) downregulated epidermal differentiation gene signatures, and impaired epidermal differentiation. PRAME OE also attenuated retinoid-induced RARE activation, growth suppression and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells possessed enrichment of epidermal differentiation gene signatures. PRAME depletion also restored retinoid-induced RARE activation, suppression of KC growth, keratinization suppression in SCC cells and cell death signaling in BCC cells. Furthermore, EZH2 inhibitors potentiated the retinoid-induced RARE activation and suppress the growth of PRAME-expressing BCC and cSCC cells. We demonstrate that PRAME confers retinoid resistance in KC, and we contend that PRAME-mediated retinoid resistance in KC may be overcome by targeting EZH2.
2025-03-17 | GSE271108 | GEO
Project description:Preferentially Expressed Antigen in Melanoma (PRAME) is frequently overexpressed in a wide variety of cancers and it has been proposed as prognostic marker for clinical outcome. It belongs to a class of non-mutated genes whose expression seems to be mostly restricted to tumor cells. Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Despite advances in the diagnosis and management of osteosarcoma, long-term survival has not envolved substantially in the past decades, justifying efforts in finding effective therapeutic targets. In order to assess transcriptome characteristics that could contribute to further comprehend PRAME association with cancer, the technique of gene expression profiling was used to compare PRAME-positive and PRAME-negative osteosarcoma samples. Keywords: disease state analysis Six tumor samples representing distinct histological classes of osteosarcoma (telangiectatic, giant cell, anaplastic, osteoblastic and chondroblastic) were included in this study. They were obtained from individual patients ranging from 5 to 29 years old. Microarray experiments were carried out using the microarray platform CodeLink (GE Healthcare). This platform utilizes bioarrays consisting of 30-base, single pre-validated oligonucleotide probe per gene target. CodeLink UniSet Human I bioarrays, containing 10,000 human transcripts, were used for all experiments. Hybridization procedures strictly followed protocols provided by the manufacturer (GE Healthcare). A total of 12 arrays were hybridized, including 6 tumor samples (3 PRAME-positive and 3 PRAME-negative) and their respective technical replicates. Arrays were scanned following the recommended scanning procedure and settings for use with CodeLink bioarrays (GE Healthcare) on GenePix 4000B Array Scanner/GenePix Pro 4.0 software (Axon Instruments).
2010-05-18 | E-GEOD-8079 | biostudies-arrayexpress
Project description:Purpose: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement the effect of all-trans retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, PRAME (preferentially expressed antigen in melanoma) has been shown to be a dominant repressor of RAR-signaling. Experimental design: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA-responsiveness by profiling gene expression in K562 cell lines. Results: Our data revealed a PRAME-expression associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models we could demonstrate that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR-signaling, which might be reversed by ATRA.
2013-03-10 | GSE43258 | GEO
Project description:Purpose: In acute myeloid leukemia (AML) without retinoic acid receptor (RAR) rearrangement the effect of all-trans retinoic acid (ATRA) is still poorly understood despite an association of NPM1 mutation and ATRA response. Recently, PRAME (preferentially expressed antigen in melanoma) has been shown to be a dominant repressor of RAR-signaling. Experimental design: Thus, we further investigated ATRA response mechanisms, especially the impact of PRAME expression on ATRA-responsiveness by profiling gene expression in K562 cell lines. Results: Our data revealed a PRAME-expression associated gene pattern to be significantly enriched for genes involved in the retinoic acid metabolic process. In leukemia cell line models we could demonstrate that retinoic acid-regulated cell proliferation and differentiation are impacted by PRAME expression. Conclusions: PRAME seems to impair differentiation and to increase proliferation likely via blocking RAR-signaling, which might be reversed by ATRA. For the cell line model GEP was performed using Affymetrix Human Genome U133plus2.0 Array technology according to the manufacturerM-bM-^@M-^Ys recommendations as previously reported. siRNA and scrRNA treated as well as ATRA treated K562 cells stemming from independent experiments were profiled. Using the BRB Array Tools software package fluorescence ratios were normalized by applying the RMA algorithm and supervised ClassComparison PathwayClassComparison analyses were performed.
2013-03-10 | E-GEOD-43258 | biostudies-arrayexpress
Project description:The human tumor antigen PRAME (Preferentially expressed antigen of melanoma) is frequently overexpressed in tumors. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumorigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. Genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at NF-Y promoters that are transcriptionally active, suggesting a role in gene activation. Our results are consistent with the involvement of the PRAME ubiquitin ligase complex in NF-Y-mediated transcriptional regulation.
2011-07-29 | GSE26439 | GEO
Project description:The human tumor antigen PRAME (Preferentially expressed antigen of melanoma) is frequently overexpressed in tumors. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumorigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. Genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at NF-Y promoters that are transcriptionally active, suggesting a role in gene activation. Our results are consistent with the involvement of the PRAME ubiquitin ligase complex in NF-Y-mediated transcriptional regulation. ChIP-seq binding profiles of PRAME (ChIP-seq using the preimmune serum was used as negative control), NFYA, and NFYB, and expression analysis by RNA-seq in K562 human leukemia cell line
2011-07-29 | E-GEOD-26439 | biostudies-arrayexpress
Project description:PRAME is a prominent member of the cancer germline antigen family of proteins, which triggers autologous T-cell mediated immune responses. Integrative genomic analysis in diffuse large B-cell lymphoma (DLBCL) uncovered recurrent, and highly focal deletions of 22q11.22 including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T-cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME down-modulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL, and PRC2-regulated genes were repressed in isogenic PRAME KO vs. PRAME wt lymphoma cell lines, with PRAME directly interacting with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects leading to PRAME and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis, and provide a preclinical rationale for synergistic therapies combining epigenetic re-programming with PRAME-targeted therapies.
2024-12-04 | GSE190403 | GEO
Project description:A novel nanobody-based TCR-like CAR-T therapy targeting PRAME for the treatment of acute myeloid leukemia
| PRJNA1428207 | ENA