Targeting PRC2 enhances the antitumor cytotoxic capacity of anti-CD19 CAR-T cells against hematological malignancies
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PROVIDER: PRJNA1164268 | ENA |
REPOSITORIES: ENA
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Project description:Chimeric Antigen Receptor (CAR) T cell therapy was adopted as a clinical modality for patients with relapsed/refractory hematological malignancies. Despite the clinical efficacy of CAR-T cell therapy, a considerable fraction of patients still relapses during the first months following CAR-T cell infusion. The limited CAR-T cell efficiency is thought to relate to epigenetic mechanisms involved in T cell suppression and dysfunction. Here, screening of multiple epigenetic inhibitors revealed that targeting PRC2 consistently enhanced the cytotoxic/effector phenotype of CD8 T cells. Notably, PRC2 inhibition promoted the differentiation of GZMB+ effector memory 19BBζ CAR-T cells and enhanced their antitumor activity both in vitro and in vivo. Consistent with their long-lasting antitumor activity, PRC2-inhibited 19BBζ CAR-T cells did not exhibit any signs of dysfunctionality/exhaustion. Furthermore, TCR restimulation along with PRC2 inhibition of patient-derived anti-CD19 CAR-T cells also induced the development of GZMB+ effector memory cells and elicited potent antitumor responses against CD19+ Daudi cells. In line with this, the gene signature derived from in-house PRC2-inhibited 19BBζ CAR-T cells was enriched in tisagenlecleucel (tisa-cel) BBζ CAR-T cell therapy responders with large B-cell lymphoma. Collectively, our results demonstrated that targeting PRC2 may be a promising approach to enhance a functional effector program in CAR-T cells against hematological malignancies.
2025-02-03 | GSE277818 | GEO
Project description:Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFNγ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFNγ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFNγ+ TPHEX. We also observed IFNγ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. Importantly, an IFNγ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFNγ+ TPHEX represent a potential target for immunotherapy of blood cancers.
2024-04-19 | GSE262306 | GEO
Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies. Total RNA was isolated from (malignant) hematopoietic cells isolated by flow cytometry based on expression of specific surface markers and from healthy non-hematopoietic cell types isolated or cultured from tissue biopsies or surgically removed specimen. From various non-hematopoietic cell types, total RNA was also isolated after 4 days of in vitro culture in the presence of IFN-γ or T-cell culture supernatant.
2016-09-01 | E-GEOD-76340 | biostudies-arrayexpress
Project description:STAG1 Mutations in Genetic Predisposition to Childhood hematological malignancies
| PRJEB52940 | ENA
Project description:Concomitant multiple hematological malignancies are rare and challenging to diagnose. They represent a unique model to explore the multistep process of oncogenesis. Here, we report the unique case of 62 years-old man with cardiac tamponade as first manifestation of ALK negative anaplastic large T-cell lymphoma (ALK- ALCL). Following chemotherapy, he showed one year later ALK- ALCL concurrent with diffuse large B-cell lymphoma (DLBCL-NOS) and acute monoblastic leukemia (AML-M5) in a single excisional lymph node. Clinical, pathological and multiomics data (whole exome and targeted deep sequencing, spatial transcriptomics) were analyzed. Two somatic TET2 gene mutations at high allele burden were shared by all three neoplasms, uninvolved bone marrow and CD34+ hematopoietic stem and progenitor cells (HSPCs). Secondary hits characterized each malignancy. ALK- ALCL (pericardial and nodal) showed TP53 and LYN deleterious mutations, DLBCL-NOS disclosed KRAS, STAT6, CREBBP and ATM alterations and AML-M5 had JAK3, PPM1D, NF1 and KMT2D mutations and a complex karyotype. Furthermore we demonstrated that spatial transcriptomics can identify the specific signatures of the three neoplasms. Two TET2 mutations at high allele burden in CD34+HSPCs conferred the favorable soil and the genotoxic stress from chemotherapy likely contributed to multiple hematological malignancies oncogenesis. Our case confirms the pathogenetic link between clonal hematopoiesis and cytotoxic T-cell lymphoma, so far only suspected. Most importantly, this is the first study to document the oncogenic phylogeny of concurrent T-, B-, and myeloid neoplasms from CD34+ HSPCs clone(s) in a single specimen.
2023-03-17 | E-MTAB-12742 | biostudies-arrayexpress
Project description:Background: Causative genes are mostly unknown for the mismatch repair-proficient category of familial colorectal cancers designated as FCCTX. Recent evidence suggests shared susceptibility factors between colorectal and hematological malignancies. Study design: We investigated 28 FCCTX families by exome sequencing, supplemented with whole genome sequencing, RNA-sequencing, and tumor studies to identify the predisposing genes. Guided by the findings, germline and somatic exomes of ~400 patients with acute leukemia, myelodysplastic syndrome, and myeloma were subsequently examined. Results: A family with hematological and solid malignancies revealed a truncating variant in the DEAH-box RNA helicase gene DHX40 co-segregating with disease in seven family members. Neoplastic tissues revealed no apparent “second hit”, implying a haploinsufficiency model of tumorigenesis. DHX40 siRNA-treated cell lines exhibited a 13% increase in aberrantly spliced transcripts vs. GAPDH-siRNA or non-target siRNA-treated cells. Two additional families showed truncating germline variants in the TDRD9 and TDRD5 genes encoding Tudor domain-containing RNA-binding proteins. In the hospital-based hematological series, 18% of germline and 28% of somatic exomes revealed possibly pathogenic DEAD/H box gene variants, including somatic variants of DHX40 in four. Conclusions: This study identifies DHX40, TDRD9, and TDRD5 as novel candidate genes for FCCTX predisposition. In the family segregating the truncating DHX40 variant, two carriers had hematological neoplasia, suggesting possible analogy to DDX41, a DEAD-box RNA helicase gene previously linked to myeloid malignancies. Our findings emphasize aberrant RNA metabolism behind FCCTX and hematological neoplasia.
2023-11-08 | GSE228991 | GEO
Project description:TET2 is one of the most frequently mutated genes in hematological malignancies. TET2 mutations are also frequently observed in healthy individuals with clonal hematopoiesis. Additional factors, such as inflammatory stress, might promote the expansion and initiate the pre-leukemic condition of Tet2 deficient hematopoietic stem cells. Antibiotics treatment is frequently used in normal individuals and patients with hematological malignancies treatment to suppress infection-induced inflammation. However, prolonged antibiotics treatment resulted in bone marrow suppression and gut microbiota alteration. In our study, we observed that the expansion of Tet2 deficient myeloid cells are positively correlated with serum cytokine levels at pre-malignant stages. We then evaluated the effect of antibiotic treatment in Tet2 deficient myeloid and lymphoid tumors in vivo. We found that antibiotics treatment suppressed the growth of Tet2 deficient malignant cells in vivo. RNA-seq analysis revealed significant changes in immune related signaling pathways (e.g., Tnf-α signaling) in antibiotics treated Tet2 deficient myeloid and lymphoid tumor cells. Suppression of Tnf-α signaling using pharmacological inhibitors partially suppressed Tet2 deficient tumor cell growth in vivo. In summary, our results suggest that the expansion of Tet2 deficient blood cells are positively associated with a pre-inflammatory condition and suppression of inflammatory pathways may attenuate the progression of TET2 inactivation-associated hematological malignancies.
2021-04-01 | GSE129886 | GEO
Project description:Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T-cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. In this study, we performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlation between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers. Microarray gene expression analysis was performed on hematological malignancies of different origins and their healthy hematopoietic counterparts as well as on healthy non-hematopoietic cell types from organs that are often targeted in Graft-versus-Host Disease (166 samples in total). Various non-hematopoietic cell types were cultured in the presence of IFN-γ or T-cell culture supernatant to allow gene expression analysis under inflammatory conditions. Malignant and healthy hematopoietic cells were isolated by flow cytometry based on expression of specific surface markers and healthy non-hematopoietic cell types were isolated or cultured from tissue biopsies or surgically removed specimen. Various non-hematopoietic cell types were in vitro cultured for 4 days in the presence of IFN-γ or T-cell culture supernatant to mimic inflammation. The dataset allows comparison of gene expression between hematological malignancies and healthy non-hematopoietic cell types to estimate efficacy and toxicity of immunotherapeutic targets for hematological malignancies.
2016-09-01 | GSE76340 | GEO
Project description:Antibiotics treatment ameliorates TET2 loss-of-function associated hematological malignancies
| PRJNA533092 | ENA
Project description:The CD161 inhibitory receptor is highly upregulated by tumor-infiltrating T cells in a number of human solid tumor types, and its ligand CLEC2D is expressed by both tumor cells and infiltrating myeloid cells. Here we assessed the role of the CD161 receptor in hematological malignancies. Systematic analysis of CLEC2D expression using the Cancer Cell Line Encyclopedia (CCLE) revealed that CLEC2D mRNA was most abundant in hematological malignancies, including B cell and T cell lymphomas as well as lymphocytic and myelogenous leukemias. CLEC2D protein was detected by flow cytometry on a panel of cell lines representing a diverse set of hematological malignancies. We therefore used yeast display to generate a panel of high-affinity, fully human CD161 monoclonal antibodies (mAbs) that blocked CLEC2D binding. These mAbs were specific for CD161 and had a similar affinity for human and non-human primate CD161, a property relevant for clinical translation. A high-affinity CD161 mAb enhanced key aspects of T cell function, including cytotoxicity, cytokine production and proliferation, against cell lines originating from patients with AML, DLBCL and Burkitt lymphoma. In humanized mouse models, this CD161 mAb enhanced T cell-mediated immunity resulting in a significant survival benefit. ScRNA-seq data demonstrated that CD161 mAb treatment enhanced expression of cytotoxicity genes by CD4 T cells as well as a tissue-resident memory program by CD4 and CD8 T cells that is associated with favorable survival outcomes in multiple human cancer types. These fully human monoclonal antibodies thus represent potential immunotherapy agents for hematological malignancies.
2024-01-02 | GSE220200 | GEO