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TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

ABSTRACT: TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

PROVIDER: PRJNA823043 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18600760.fastq.gz	Fastqsanger.gz
	SRR18600761.fastq.gz	Fastqsanger.gz
	SRR18600762.fastq.gz	Fastqsanger.gz
	SRR18600763.fastq.gz	Fastqsanger.gz
	SRR18600764.fastq.gz	Fastqsanger.gz

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TGF-β and CIS inhibition overcomes NK cell suppression to restore anti-tumor immunity

Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.

2022-04-11 | GSE200134 | GEO

Activin A and NK cell function

Project description:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.

2020-04-06 | PXD011672 | Pride

Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells

Project description:Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-b (TGF-b) as a cell-autonomous driver for NK cell tissue-residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-β was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-β was redundant in tumors, our study revealed that NK cell-derived TGF-β allowed expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-β1, which is relevant for anti-viral immunity.

2024-11-21 | GSE282148 | GEO

Profiling and Rewiring Dysfunctional NK cells to Restore Anti-Tumor Activity

Project description:Profiling and Rewiring Dysfunctional NK cells to Restore Anti-Tumor Activity

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MiRNA expression variation in primary NK cells treated with TGF-β1

Project description:Human NK cells activity against cancer cells is deeply suppressed by TGF-β1, an immunomodulatory cytokine that is released and activated in the tumor microenvironment. Moreover, our previous data showed that TGF-β1 modifies the chemokine receptor repertoire of NK cells. In particular, it decreases the expression of CX3CR1 that drives these effectors toward peripheral tissues, including tumor sites. In order to identify possible mechanisms mediating chemokine receptors modulation, we analyzed the miRNA profile of TGF-β1-treated primary NK cells. The analysis pointed out miR-27a-5p as a possible modulator of CX3CR1. We demonstrated the functional interaction of miR-27a-5p with the 3’ untranslated region (3’UTR) of CX3CR1 mRNA by two different experimental approaches: by the use of a luciferase assay based on a reporter construct containing the CX3CR1 3’UTR and by transfection of primary NK cells with a miR-27a-5p inhibitor. We also showed that the TGF-β1-mediated increase of miR-27a-5p expression is a consequence of miR-23a-27a-24-2 cluster induction. Moreover, we demonstrated that miR-27a-5p down-regulates the surface expression of CX3CR1. Finally we showed that Neuroblastoma cells induced in resting NK cells a downregulation of the CX3CR1 expression that was paralleled by a significant increase of miR-27a-5p expression. Therefore, the present study highlights miR-27a-5p as a pivotal TGF-β1-induced regulator of CX3CR1 expression.

2017-05-11 | GSE98769 | GEO

TGF-β1 induces bone marrow NK cells dysfunction

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Subverting TGF-β suppression by knocking out SMAD4 enhances human NK cell anti-tumor function

Project description:Engineering TGF-β-resistant NK cells for cancer immunotherapy.

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IL-2 and TGF-b1 promote regulatory activity in NK cells following Hematopoietic Stem Cell Transplantation

Project description:Natural Killer(NK) cell activity is influenced by cytokines and microenvironment factors, resulting in remarkably diverse functions ranging from contributing to inflammatory responses to instead inhibiting T cell and B cell activity, thereby serving as rheostats of adaptive immunity. Using scRNAseq, we identified a TGFb1highCD56brightNK cell population associated with protection from acute Graft-versus-Host Disease. We further define a role for the combination of IL-2 and TGF-b in promoting NK cells to acquire a regulatory phenotype. ‘Induced’ regulatory NK cells produce high amounts of TGF-b1, inhibited T cells, could promote naïve T cells differentiation into regulatory T cells, and exhibited a unique transcriptional program that includes expression of IKZF2(HELIOS) and ZNF683(HOBIT). This phenotype was not stable, and induced regulatory NK cells lost the ability to secrete TGF-b1 upon exposure to different cytokines. These findings define protective CD56brightNK cells in Hematopoietic Stem Cell Transplant, and support IL-2 and TGF-b1 promote regulatory NK cells.

2024-11-12 | GSE255298 | GEO

Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells

Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human iPSCs to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knock out TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with CARs that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-b activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies which express high levels of TGF-β.

2024-04-08 | GSE263459 | GEO

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

Project description:Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells

| PRJNA524164 | ENA