Absence of NKG2D ligands defines human leukaemia stem cells and mediates their immune evasion
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ABSTRACT:
PROVIDER: PRJNA525870 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8690540_1.fastq.gz | Fastqsanger.gz | |||
| SRR8690540_2.fastq.gz | Fastqsanger.gz | |||
| SRR8690541_1.fastq.gz | Fastqsanger.gz | |||
| SRR8690541_2.fastq.gz | Fastqsanger.gz | |||
| SRR8690532_1.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:NKG2D ligands are broadly expressed in cancer. To exploit this, we engineered an adaptor chimeric antigen receptor (CAR) termed NKG2D / Dap10-12 in which NKG2D is co-expressed with a fusion of Dap10 and the Dap12 endodomain. Dap10 was deployed to provide co-stimulation while Dap12 delivers an activation signal via a single immunoreceptor tyrosine-based activation motif (ITAM). NKG2D / Dap10-12 T-cells elicited compelling anti-tumor activity in several solid tumor xenograft models. Disease eradication was accompanied by sustained functional persistence, indicated by reproducible protection from secondary tumor re-challenge. Anti-cancer activity was consistently superior to an analog of a clinical stage linear CAR comprising an NKG2D-CD3 fusion. Mechanistically, functionality of NKG2D / Dap10-12 CAR T-cells was underpinned by transcriptomic re-programming to increase oxidative phosphorylation and ribosome biosynthesis..
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Project description:Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), that are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored how soluble NKG2DL affected NKG2D-CAR T cells´ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells. In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by soluble NKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.
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Project description:Metabolic-associated fatty liver disease (MAFLD) comprises a spectrum of clinical entries ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of non-alcoholic steatohepatitis (NASH) that may lead to fibrosis and hepatocellular carcinoma. What triggers inflammation in MAFLD is unknown. We find that lipid accumulation in hepatocytes induces expression of ligands for the activating immune receptor NKG2D. Tissue-resident innate-like T cells are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit pro-inflammatory cells into the liver, causing NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in a dietary model for NASH and had a marked decrease in the incidence of hepatic tumors. Importantly, the frequency of IL-17A+ γδ T cells in the blood MAFLD patients correlated with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in context of MAFLD.
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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
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