Modulation of intrinsic inhibitory checkpoints using nano‐carriers to unleash NK cell activity

Biber, Guy; Sabag, Batel; Raiff, Anat; Ben‐Shmuel, Aviad; Puthenveetil, Abhishek; Benichou, Jennifer I. C.; Jubany, Tammir; Levy, Moria; Killner, Shiran; Barda‐Saad, Mira

doi:10.15252/emmm.202114073

Cited by 32 publications

(39 citation statements)

References 84 publications

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“…We recently showed that ARF and Protein Kinase C (PKC)θ play an important role in determining the SHP-1 conformational structure and its impact on NK cell activity [ 9 , 33 ]. Along these lines, we also demonstrated that silencing of SHP-1 upon inhibitory synapse engagement improves NK cell cytotoxic potential [ 34 ]. In the current study, we demonstrate that the SHP-1-ARF axis is governed by WASp, the actin nucleation-promoting factor that dictates the NK cell immune response.…”

Section: Discussionmentioning

confidence: 99%

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Actin Retrograde Flow Regulated by the Wiskott–Aldrich Syndrome Protein Drives the Natural Killer Cell Response

Sabag

Levy

Kivelevitz

et al. 2022

Cancers

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Understanding the crosstalk between natural killer (NK) cells and the tumor microenvironment (TME) has enhanced the potential of exploiting the interplay between activation and inhibition of NK cells for immunotherapy. This interaction is crucial for understanding how tumor cells escape NK cell immune surveillance. NK cell dysfunction is regulated by two molecular mechanisms, downregulated activating receptor ligand expression on the tumor cells, and upregulated inhibitory signals delivered to NK cells. Recent studies demonstrated the role of mechanotransduction in modulating NK cell responses in the TME. The immunological synapse represents a functional interface between the NK cell and its target, regulated by Actin Retrograde Flow (ARF), which drives the adhesion molecules and receptors toward the central zone of the immunological synapse (IS). Here, we further characterize the role of ARF in controlling the immune response of NK cells, using CRISPR/cas9-mediated Wiskott–Aldrich Syndrome protein (WASp) gene silencing of NK cells. We demonstrate that WASp regulates ARF velocity, affecting the conformation and function of the key NK inhibitory regulator, SH2-domain containing protein tyrosine phosphatase-1 (SHP-1), and consequently, the NK cell response. Our results demonstrate the potential of modulating the biophysical and intracellular regulation of NK activation as a promising approach for improving immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…Cells were centrifuged, supernatant was cleared, and the cells were re-suspended in lysis buffer as previously described [ 9 , 33 , 34 ]. Cells were placed on ice for 30 min and then centrifuged.…”

Section: Methodsmentioning

confidence: 99%

Actin Retrograde Flow Regulated by the Wiskott–Aldrich Syndrome Protein Drives the Natural Killer Cell Response

Sabag

Levy

Kivelevitz

et al. 2022

Cancers

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Section: Cbl-b and C-cblmentioning

confidence: 99%

“…Recently, a non-viral lipid nanoparticle (NP)-based delivery system containing small interfering RNAs (siRNAs) has successfully silenced the main intracellular NK checkpoints, c-Cbl, Cbl-b, and SHP-1, in vivo [28]. Such checkpoint blockade unleashes NK cell activity and enhances NK cytotoxicity in the tumor microenvironment [28]. Besides, since these nanoparticles directly target NK cells in vivo, there is no need for ex vivo expansion of NK cells, which has been a major drawback of current NK cell-based immunotherapies [28].…”

Section: Cbl-b and C-cblmentioning

confidence: 99%

“…Such checkpoint blockade unleashes NK cell activity and enhances NK cytotoxicity in the tumor microenvironment [28]. Besides, since these nanoparticles directly target NK cells in vivo, there is no need for ex vivo expansion of NK cells, which has been a major drawback of current NK cell-based immunotherapies [28]. As a result, this innovative NP-based delivery system could be a useful tool for future NK cell-based cancer therapies.…”

Section: Cbl-b and C-cblmentioning

confidence: 99%

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Unleashing Anti-Tumor Activity of Natural Killer Cells Via Modulation of Immune Checkpoints Receptors and Molecules

Fang¹

2022

HSET

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As vital innate lymphocytes, natural killer (NK) cells suppress cancer progression chiefly by inducing cell lysis and secreting pro-inflammatory cytokines. NK cell activation relies on the balance between inhibitory and stimulating signals mediated by a wide range of surface receptors. Specific receptors initiate intracellular signaling pathways, which are negatively regulated by specific checkpoint molecules. Synergistic activation is controlled by Cbl proteins and GSK-3β, while the downstream signaling pathways induced by ITIM-bearing receptors are regulated by SHP-1. These intracellular NK checkpoints are attractive targets for immune checkpoint blockade therapies, but not enough attention has been given. Hence, this paper discusses the major signaling pathways regulated by the intracellular checkpoints and their potential clinical application. The current progress in the investigation of NK checkpoint receptors is also summarized. This paper aims to promote the development of novel immunotherapies that optimize the tumor-suppressive activity of NK cells while suppressing tumor immunological evasion.

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Nanomaterial‐Boosted Tumor Immunotherapy Through Natural Killer Cells

Zhan

Guo

Shen

et al. 2022

Advanced NanoBiomed Research

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Natural killer (NK)‐cell immunotherapy as an alternative to T‐cell immunotherapy has been widely used in clinical cell immunotherapy of various tumors. Despite the surprising findings, the widespread applications of NK cells are still limited by the insufficient expansion and short lifespan of adoptive NK cells in vivo, the poor penetration of NK cells in solid tumors, as well as the immunosuppressive tumor microenvironment that may cause the inactivation of NK cells. Fortunately, the emergence of nanomaterials provides many opportunities to address these vexing problems, thus overcoming the barriers faced by NK cells and promoting the tumor inhibitory efficacy of NK cells. Herein, the recent advances in the rational design of nanomaterials for boosting the NK cell‐based immunotherapy, mainly through enhancing NK cell engagement with tumors, boosting NK cell activation or expansion, as well as redirecting NK cells to tumor cells, are reviewed. Lastly, the design and preparation of next‐generation nanomaterials that aim to further boost the NK cell‐based immunotherapy are briefly discussed.

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Modulation of intrinsic inhibitory checkpoints using nano‐carriers to unleash NK cell activity

Cited by 32 publications

References 84 publications

Actin Retrograde Flow Regulated by the Wiskott–Aldrich Syndrome Protein Drives the Natural Killer Cell Response

Actin Retrograde Flow Regulated by the Wiskott–Aldrich Syndrome Protein Drives the Natural Killer Cell Response

Unleashing Anti-Tumor Activity of Natural Killer Cells Via Modulation of Immune Checkpoints Receptors and Molecules

Nanomaterial‐Boosted Tumor Immunotherapy Through Natural Killer Cells

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