Dataset Information

Styk1 expression is a hallmark of murine NK cells and other NK1.1⁺ subsets but is dispensable for NK-cell development and effector functions.

ABSTRACT: To gain insight into the biology of NK cells, others and we previously identified the NK-cell signature, defined as the set of transcripts which expression is highly enriched in these cells compared to other immune subtypes. The transcript encoding the Serine/threonine/tyrosine kinase 1 (Styk1) is part of this signature. However, the role of Styk1 in the immune system is unknown. Here, we report the generation of a novel transgenic mouse model, in which Styk1 expression is invalidated and replaced by an EGFP reporter cassette. We demonstrated that Styk1 expression is a hallmark of NK cells and other NK1.1 expressing cells such as liver type 1 innate lymphoid cells (ILC1) and NK1.1⁺ γδ T cells. Styk1 expression is maintained by IL-15 in NK cells and negatively correlates with the expression of educating NK-cell receptors. Analysis of phosphorylation levels of mTOR substrates suggested that Styk1 could moderately contribute to the activity of the PI3K/Akt/mTOR pathway. However, Styk1-deficient NK cells develop normally and have normal in vitro and in vivo effector functions. Thus Styk1 expression is a hallmark of NK cells, ILC1 and NK1.1⁺ T cells but is dispensable for their development and immune functions.

SUBMITTER: Fauteux-Daniel S

PROVIDER: S-EPMC8351758 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Styk1 expression is a hallmark of murine NK cells and other NK1.1<sup>+</sup> subsets but is dispensable for NK-cell development and effector functions.

Fauteux-Daniel Sébastien S Faure Fabrice F Marotel Marie M Geary Clair C Daussy Cécile C Sun Joseph C JC Walzer Thierry T

European journal of immunology 20190215 5

To gain insight into the biology of NK cells, others and we previously identified the NK-cell signature, defined as the set of transcripts which expression is highly enriched in these cells compared to other immune subtypes. The transcript encoding the Serine/threonine/tyrosine kinase 1 (Styk1) is part of this signature. However, the role of Styk1 in the immune system is unknown. Here, we report the generation of a novel transgenic mouse model, in which Styk1 expression is invalidated and replac ...[more]

PMID: 30690705

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Project description:BackgroundT cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.MethodsIn this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.ResultsThe screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.ConclusionsThese findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.

Dataset Information

Styk1 expression is a hallmark of murine NK cells and other NK1.1⁺ subsets but is dispensable for NK-cell development and effector functions.

Publications

Styk1 expression is a hallmark of murine NK cells and other NK1.1<sup>+</sup> subsets but is dispensable for NK-cell development and effector functions.

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Dataset Information

Styk1 expression is a hallmark of murine NK cells and other NK1.1+ subsets but is dispensable for NK-cell development and effector functions.

Publications

Styk1 expression is a hallmark of murine NK cells and other NK1.1<sup>+</sup> subsets but is dispensable for NK-cell development and effector functions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Styk1 expression is a hallmark of murine NK cells and other NK1.1⁺ subsets but is dispensable for NK-cell development and effector functions.