Increased expression of NKG2D ligands in BrafV600E-driven thyroid cancer cells with β-catenin ablation
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ABSTRACT:
PROVIDER: PRJNA856699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20027622.fastq.gz | Fastqsanger.gz | |||
| SRR20027623.fastq.gz | Fastqsanger.gz | |||
| SRR20027624.fastq.gz | Fastqsanger.gz | |||
| SRR20027625.fastq.gz | Fastqsanger.gz | |||
| SRR20027626.fastq.gz | Fastqsanger.gz |
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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:Absence of NKG2D ligands defines human leukaemia stem cells and mediates their immune evasion
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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.
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Project description:BRAFV600E mutation is the most frequent molecular event in papillary thyroid carcinoma. The relation of this genetic alteration with the factors od poor prognosis has been reported as well as its influence on PTC gene signature. However human material disables distinction of cancer causes from its effect. We used our transgenic mouse model of papillary thyroid carcinoma induced by the BRAFV600E mutation to select BRAFV600E-specifi gene signature which was than compared to human material The human microarray data were obtained for: 27 papillary thyroid carcinomas including 18 BRAF(+), 8 RET(+), 1 RAS(+); 18 apparently healthy thyroids. In order to find BRAFV600E-specific gene signature data obtained from our transgenic mouse model of PTC were compared to human material. The analyses were performed taking into account not only the BRAF mutation but also other PTC initiating events including RET rearrangements and RAS poin mutations. Morover the microarray data were validated with the QPCR reaction.
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Project description:BRAFV600E mutation is the most frequent molecular event in papillary thyroid carcinoma. The relation of this genetic alteration with the factors od poor prognosis has been reported as well as its influence on PTC gene signature. However human material disables distinction of cancer causes from its effect. We used our transgenic mouse model of papillary thyroid carcinoma induced by the BRAFV600E mutation to select BRAFV600E-specifi gene signature which was than compared to human material
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