Absence of NKG2D ligands defines human leukaemia stem cells and mediates their immune evasion
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PROVIDER: PRJNA525870 | ENA |
REPOSITORIES: ENA
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Project description:Patients with acute myeloid leukaemia (AML) often achieve remission yet subsequently die of disease relapse, which is commonly driven by chemotherapy-resistant leukaemic stem cells (LSCs). LSCs are defined by their capacity to initiate leukaemia in immuno-compromised mice. This precludes an analysis of their interaction with lymphocytes as components of anti-tumour immunity, which LSCs must escape in order to induce cancer7. Here we propose that stemness and immune evasion are closely intertwined in human AML. Using human AML xenograft and syngeneic mouse leukemia models, we show that ligands of the danger detector NKG2D, a critical mediator of anti-tumour immunity by cytotoxic lymphocytes such as natural killer (NK) cells, are generally expressed on bulk AML cells but not on LSCs. Functional LSCs can be isolated by their lack of NKG2D ligand (NKG2DL) expression, even in human AMLs not expressing the conventional LSC marker CD34. NKG2DL expressing AML cells are cleared by NK cells while NKG2DLneg leukaemic cells isolated from the same individuals escape NK cell killing. These NKG2DLneg AML cells show an immature morphology, display molecular and functional stemness characteristics, can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplants (PDX). Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) negatively regulates NKG2DL and PARP1 inhibition (PARPi) induces NKG2DL surface expression in LSCs. Consequently, co-treatment with PARPi and NK cells suppresses leukaemogenesis in PDX models. Low expression of surface NKG2DL as well as high PARP1 expression are associated with inferior clinical outcome in patients with AML. In summary, our data link the concept of LSCs to immune escape and indicate absence of immunostimulatory NKG2DL as a novel method to identify LSCs across genetic AML subtypes. Moreover, we provide a strong rationale for targeting therapy resistant LSCs by PARP1 inhibition rendering them amenable to NK cell control in vivo.
2019-08-13 | GSE127959 | GEO
Project description:Patients with acute myeloid leukaemia (AML) often achieve remission after therapy, but subsequently die of relapse1 that is driven by chemotherapy-resistant leukaemic stem cells (LSCs)2,3. LSCs are defined by their capacity to initiate leukaemia in immunocompromised mice4. However, this precludes analyses of their interaction with lymphocytes as components of anti-tumour immunity5, which LSCs must escape to induce cancer. Here we demonstrate that stemness and immune evasion are closely intertwined in AML. Using xenografts of human AML as well as syngeneic mouse models of leukaemia, we show that ligands of the danger detector NKG2D-a critical mediator of anti-tumour immunity by cytotoxic lymphocytes, such as NK cells6-9-are generally expressed on bulk AML cells but not on LSCs. AML cells with LSC properties can be isolated by their lack of expression of NKG2D ligands (NKG2DLs) in both CD34-expressing and non-CD34-expressing cases of AML. AML cells that express NKG2DLs are cleared by NK cells, whereas NKG2DL-negative leukaemic cells isolated from the same individual escape cell killing by NK cells. These NKG2DL-negative AML cells show an immature morphology, display molecular and functional stemness characteristics, and can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplant models. Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) represses expression of NKG2DLs. Genetic or pharmacologic inhibition of PARP1 induces NKG2DLs on the LSC surface but not on healthy or pre-leukaemic cells. Treatment with PARP1 inhibitors, followed by transfer of polyclonal NK cells, suppresses leukaemogenesis in patient-derived xenotransplant models. In summary, our data link the LSC concept to immune escape and provide a strong rationale for targeting therapy-resistant LSCs by PARP1 inhibition, which renders them amenable to control by NK cells in vivo.
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Project description:This work uncovers a druggable chromatin crosstalk that defines tumor innate immune response and enables immune evasion.
2022-10-08 | GSE186239 | GEO
Project description:In vivo studies indicate that human acute myeloid leukaemia (AML) originates from subpopulations of neoplastic cells with stem cell properties, thereby laying the foundation for the cancer stem cell concept. For clinically apparent disease to occur, cancer-initiating cells must also escape immune control. Here we show that stemness and immune evasion are closely intertwined in AML. Patients with AML harbour leukaemic subpopulations that lack expression of ligands for the danger detector NKG2D, a critical mediator of immune surveillance, which stimulates anti-tumour immunity by cytotoxic lymphocytes such as natural killer (NK) cells. We compared NKG2DLneg and NKG2DLpos subfractions from n=5 patients (each measured in triplicates) and found that NKG2DLneg cells displayed amongst others stemness characteristics.Our findings identify immune privilege as a general feature of LSCs, and provide a conceptual framework for the integration of two central hypotheses of cancer development – the concepts of cancer stem cells and immune escape
2019-03-15 | GSE127200 | GEO
Project description:IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia
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Project description:BRAFV600E mutation frequently occurs in papillary thyroid cancer (PTC). β-catenin, encoded by CTNNB1, is a key downstream component of canonical Wnt signaling pathway and is often overexpressed in PTC. BRAFV600E-driven PTC tumors rely on Wnt/β-catenin signaling to sustain their growth and progression. In the present study, we investigated the tumorigenicity of thyroid cancer cells derived from BrafV600E PTC mice after Ctnnb1 ablation (BVE-Ctnnb1null). Remarkably, the tumorigenic potential of BVE-Ctnnb1null tumor cells was lost in nude mice. RNA-Seq analysis of the BVE-Ctnnb1null tumor cells showed up-regulation of NKG2D receptor activating ligands (H60a, H60b, H60c, Raet1a, Raet1b, Raet1c, Raet1d, Raet1e and Ulbp1) and down-regulation of inhibitory MHC class I molecules H-2L and H-2K2 in the BVE-Ctnnb1null tumor cells. In vitro cytotoxicity assay demonstrated that BVE-Ctnnb1wt tumor cells were resistant to NK cell-mediated cytotoxicity whereas BVE-Ctnnb1null tumor cells were sensitive to NK cell-mediated killing. Furthermore, overexpression of any one of these NKG2D ligands in the BVE-Ctnnb1wt cell line resulted in significant reduction of tumor growth in nude mice. Our results indicate that active β-catenin signaling inhibits NK cell-mediated immune response against thyroid cancer cells. Targeting β-catenin signaling pathway may have significant therapeutic benefit for thyroid cancer by not only inhibiting tumor growth but also enhancing host immune surveillance.
2023-02-09 | GSE207695 | GEO
Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.
2023-03-11 | PXD032980 | Pride
Project description:We discovered that KRAS-mutant lung adenocarcinomas (LADC) co-opt CREB in order to evade the innate immune system: KRAS-driven CREB activation in LADC suppresses the expression of CXCR1 ligands that would otherwise recruit neutrophils to the tumor site. CREB was overexpressed in murine KRAS-mutant LADC, pulmonary Creb1-deletion inhibited disease development, and Creb1-overexpression boosted the tumorigenicity of KRAS-mutant cells. Conditional Creb1 deletion in Kras-mutant LADC cells caused overexpression of CXCR1/2 ligands, and lung tumor-bearing Creb1-deleted mice displayed increased pulmonary neutrophils. Cxcr1-deficient mice were selectively permissive to KRAS-mutant tumor growth and showed defective neutrophil recruitment. The pro-tumor effects of CREB required intact host-Cxcr1 and those of host-Cxcr1 necessitated mutant KRAS in cancer cells. Pharmacologic CREB blockade prevented tumor growth and restored neutrophil recruitment only when initiated before immune evasion of KRAS-mutant LADC cells. CREB and CXCR1 expression were respectively restricted to tumor and stromal cells of human LADC, while CREB-controlled genes profoundly impacted survival. In summary, CREB-mediated immune evasion of KRAS-mutant LADC rests on signaling to myeloid CXCR1 and is actionable.
2023-08-19 | GSE156513 | GEO
Project description:Somatic mutations can lead to the transformation of healthy cells into malignant cells and allow their evasion from immune surveillance. To uncover genes that play a role in the detection and lysis of tumor cells by natural killer (NK) cells, a B lymphoblastoid cell line was subjected to a genome-wide CRISPR screen. Deletion of genes for death receptor and ligands for NK activation receptors was found in cells that survived incubation with primary NK cells. Among the top hits that facilitated NK evasion was SPPL3, a gene for an endoprotease that cleaves transmembrane glycosyl transferases. SPPL3-deficient cells accumulated glycosyl transferases, such as MGAT5, and displayed increased N-glycosylation. Binding of NK receptors NKG2D and CD2 to their corresponding ligands MICB and CD58, and binding of rituximab to CD20, was disrupted. Inhibition of N-glycan maturation restored receptor binding and sensitivity to NK cells. To investigate the cause of this resistant phenotype, a secondary CRISPR screen using a glycosylation-focused library was performed in SPPL3-deficient cells. This screen identified transferases that promote the formation of highly branched N-glycans and N-acetyl-lactosamine (LacNAc) extensions as key regulators that prevent killing. A significant enrichment of poly-LacNAc-containing tetra-antennary species was confirmed by glycoproteomic analysis. These findings provide a basis for understanding why SPPL3 deletions have been linked to cancer.
2024-03-19 | PXD040769 | Pride
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE260919 | GEO