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Epigenetic priming induces cancer testis antigens and human endogenous retroviruses in glioma for enhanced T cell responses at single cell resolution (methylation)

ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of NY-ESO-1 in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres, we demonstrate in vitro that basal NY-ESO-1 expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing and renders NY-ESO-1 an inducible tumor antigen. Targeting of DAC-induced NY-ESO-1 in primary GBM cells promotes specific and polyfunctional NY-ESO-1 TCR-T cell responses. DAC further upregulates other tumor-associated cancer testis antigens concomitantly with tumor-intrinsic reactivation of human endogenous retroviruses (hERV) and type I interferon. Overall, we demonstrate that DAC promotes an inducible tumor antigen and enhances T cell functionality against GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261190 | GEO | 2024/06/04

REPOSITORIES: GEO

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Epigenetic priming induces cancer testis antigens and human endogenous retroviruses in glioma for enhanced T cell responses at single cell resolution (scRNA-Seq)

Project description:Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of NY-ESO-1 in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres, we demonstrate in vitro that basal NY-ESO-1 expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing and renders NY-ESO-1 an inducible tumor antigen. Targeting of DAC-induced NY-ESO-1 in primary GBM cells promotes specific and polyfunctional NY-ESO-1 TCR-T cell responses. DAC further upregulates other tumor-associated cancer testis antigens concomitantly with tumor-intrinsic reactivation of human endogenous retroviruses (hERV) and type I interferon. Overall, we demonstrate that DAC promotes an inducible tumor antigen and enhances T cell functionality against GBM.

2024-06-03 | GSE261188 | GEO

Epigenetic priming induces cancer testis antigens and human endogenous retroviruses in glioma for enhanced T cell responses at single cell resolution (bulk RNA-Seq)

2024-06-03 | GSE261187 | GEO

Genome-wide maps of chromatin state in human primary CAR-T cells [scRNA-seq]

Project description:We report the single-cell transcriptomic profile of human primary T cells specifc for NY-ESO-1.

2022-09-09 | GSE213015 | GEO

TCR affinity-dependent functional inhibition via PD-1 and SHP-1 phosphatase

Project description:To investigate gene expression changes associated with stimulation of TCRs of different affinity, primary CD8 T cells were transduced with sequence optimized TCRs of various affinities and stimulated for 6h. Gene expression was measured at baseline (0h) and after 6h after stimulation with low dose NY-ESO-1 multimer

2013-02-11 | E-GEOD-42922 | biostudies-arrayexpress

Large-scale assessment of the gliomasphere model system

Project description:Some aspects of the gene expression-based classification method were robust because the gliomasphere cultures retained their classification over many passages, and IDH1 mutant gliomaspheres were all proneural. While gene expression of a subset of gliomasphere cultures was more like the parent tumor than any other tumor, gliomaspheres did not always harbor the same classification as their parent tumor. Classification was not associated with whether a sphere culture was derived from primary or recurrent GBM or associated with the presence of EGFR amplification or rearrangement. Unsupervised clustering of gliomasphere gene expression distinguished 2 general categories (mesenchymal and nonmesenchymal), while multidimensional scaling distinguished 3 main groups and a fourth minor group. Unbiased approaches revealed that PI3Kinase, protein kinase A, mTOR, ERK, Integrin, and beta-catenin pathways were associated with in vitro measures of proliferation and sphere formation. Associating gene expression with gliomasphere phenotypes and patient outcome, we identified genes not previously associated with GBM: PTGR1, which suppresses proliferation, and EFEMP2 and LGALS8, which promote cell proliferation. This comprehensive assessment reveals advantages and limitations of using gliomaspheres to model GBM biology, and provides a novel strategy for selecting genes for future study.

2017-05-27 | GSE98995 | GEO

Vaccine Therapy With or Without Sirolimus in Treating Patients With NY-ESO-1 Expressing Solid Tumors

Project description:This phase I trial studies the side effects and best schedule of vaccine therapy with or without sirolimus in treating patients with cancer-testis antigen (NY-ESO-1) expressing solid tumors. Biological therapies, such as sirolimus, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from a person’s white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells that express NY-ESO-1. Infusing the vaccine directly into a lymph node may cause a stronger immune response and kill more tumor cells. It is not yet known whether vaccine therapy works better when given with or without sirolimus in treating solid tumors.

| 2119578 | ecrin-mdr-crc

Cell fusion with type 2 macrophage induce heterogeneity of melanoma cells that potentiate immunological escape from cytotoxic T lymphocytes

Project description:Evasion from immunity is a major obstacle for achievement of successful cancer immunotherapy. Hybrids derived from cell-cell fusion is a theory associated with tumor heterogeneity and progression by conferring novel properties to tumor cells, such as drug resistance or metastatic capacity; however, its impact on immune evasion remains still unknown. Here, we investigated the potency of hybrids in immune evasion using tumor-macrophage hybrids. Hybrids were established by co-culture of a melanoma cell line, A375 and type 2 macrophages. The hybrids showed higher migration ability and higher tumorigenicity than those of the parental melanoma cells. We found that the hybrids were less sensitive to T cell receptor (TCR) specific for NY-ESO-1 transduced T cells (TCR-T cells) than parental melanoma cells, although hybrids and parental melanoma cells showed equivalent NY-ESO-1 expression. An in vitro tumor heterogeneity model revealed that TCR-T cells preferentially killed parental cells than hybrids and the survival rate of hybrids were higher than that in parental cells indicating hybrids evade from killing by TCR-T cells efficiently. A single cell analysis data set revealed that a few macrophage cells expressed melanoma differentiation antigens including gp100, MART-1 and tyrosinase, indicating hybrids exist in primary melanoma, and number of potential hybrids were corelated with poorer response to immune checkpoint blockade. These results provide evidence that melanoma-macrophage fusion has a role in tumor heterogeneity and immune evasion.

2023-05-04 | GSE210578 | GEO

Gene Fusion Discovery through RNA Sequencing of Human Glioblastoma Stem Cell Lines

Project description:<p>We used massively parallel, paired-end sequencing of expressed transcripts (RNA-seq) to detect novel gene fusions in short-term cultures of glioma stem-like cells freshly isolated from nine patients carrying primary glioblastoma multiforme (GBM). The culture of primary GBM tumors under serum-free conditions selects cells that retain phenotypes and genotypes closely mirroring primary tumor profiles as compared to serum-cultured glioma cell lines that have largely lost their developmental identities.</p>

| phs000505 | dbGaP

Tumor gene expression analysis of synovial sarcoma patients treated with NY-ESO-1 TCR T cells (NCT01343043) [Immune]

Project description:Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. Biomarkers predictive of response and resistance remain to be better defined. In 45 synovial sarcoma patients, we analyzed the association of response to lete-cel (NCT01343043) with tumor gene expression. Analysis of tumor samples post-treatment illustrated lete-cel infiltration and decreased expression of macrophage genes, suggesting remodeling of the tumor microenvironment.

2022-05-16 | GSE202978 | GEO

Tumor gene expression analysis of synovial sarcoma patients treated with NY-ESO-1 TCR T cells (NCT01343043) [Pathway]

2022-05-16 | GSE202979 | GEO

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