Hexamethylene bisacetamide impairs NK cell-mediated clearance of acute T lymphoblastic leukemia cells and HIV-1-infected T cells that exit viral latency

Giuliani, Erica; Desimio, Maria Giovanna; Doria, Margherita

doi:10.1038/s41598-019-40760-x

Cited by 9 publications

(7 citation statements)

References 68 publications

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“…Latency reversing agents (LRAs), known as drugs able to induce viral production and unmask latently-infected cells, represent a promising clinical approach to cure HIV-1 [198,199]. LRAs promote “shock-and-kill” immune-mediated mechanisms, including those dependent on NK cells [200,201,202]. Interestingly, in the context of HIV-1, some LRAs have the potential to induce DNAM-1 ligands on CD4 + T cells [200]; therefore, it will be important to evaluate the contribution of DNAM-1-mediated responses of NK cells against HIV-1 infection upon the “shock-and-kill” triggering.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?

Cifaldi

Doria

Cotugno

et al. 2019

IJMS

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Natural Killer (NK) cells play a critical role in host defense against viral infections. The mechanisms of recognition and killing of virus-infected cells mediated by NK cells are still only partially defined. Several viruses induce, on the surface of target cells, the expression of molecules that are specifically recognized by NK cell-activating receptors. The main NK cell-activating receptors involved in the recognition and killing of virus-infected cells are NKG2D and DNAM-1. In particular, ligands for DNAM-1 are nectin/nectin-like molecules involved also in mechanisms allowing viral infection. Viruses adopt several immune evasion strategies, including those affecting NK cell-mediated immune surveillance, causing persistent viral infection and the development of virus-associated diseases. The virus’s immune evasion efficacy depends on molecules differently expressed during the various phases of infection. In this review, we overview the molecular strategies adopted by viruses, specifically cytomegalovirus (CMV), human immunodeficiency virus (HIV-1), herpes virus (HSV), Epstein-Barr virus (EBV) and hepatitis C virus (HCV), aiming to evade NK cell-mediated surveillance, with a special focus on the modulation of DNAM-1 activating receptor and its ligands in various phases of the viral life cycle. The increasing understanding of mechanisms involved in the modulation of activating ligands, together with those mediating the viral immune evasion strategies, would provide critical tools leading to design novel NK cell-based immunotherapies aiming at viral infection control, thus improving cure strategies of virus-associated diseases.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?

Cifaldi

Doria

Cotugno

et al. 2019

IJMS

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“…Many tumors have been known to overexpress stress-induced ligands that can stimulate NK cell activity (2,3). Like many of these tumors, Jurkat cells have been shown to express NK cell ligands (22,23). These ligands could potentially synergize with costimulatory receptor signaling to promote NK cell-mediated cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

A functional mammalian display screen identifies rare antibodies that stimulate NK cell–mediated cytotoxicity

Kang

Kadoch

Rubenstein

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Therapies that boost the antitumor immune response have shown a great deal of success. Although most of these therapies have focused on enhancing T cell functions, there is a growing interest in developing therapies that can target other immune cell subsets. Like T cells, natural killer (NK) cells are cytotoxic effector cells that play a key role in the antitumor response. To advance the development of NK-based therapies, we developed a functional screen to rapidly identify antibodies that can activate NK cells. We displayed antibodies on a mammalian target cell line and probed their ability to stimulate NK cell–mediated cytotoxicity. From this screen, we identified five antibodies that bound with high affinity to NK cells and stimulated NK cell–mediated cytotoxicity and interferon-γ (IFN-γ) secretion. We demonstrate that these antibodies can be further developed into bispecific antibodies to redirect NK cell–mediated cytotoxicity toward CD20+ B cell lymphoma cells and HER2+ breast cancer cells. While antibodies to two of the receptors, CD16 and NCR1, have previously been targeted as bispecific antibodies to redirect NK cell–mediated cytotoxicity, we demonstrate that bispecific antibodies targeting NCR3 can also potently activate NK cells. These results show that this screen can be used to directly identify antibodies that can enhance antitumor immune responses.

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“…When expression of NK cell activating receptors was analyzed, various HDACis showed diverse negative effects, the worse being observed with Panobinostat that downregulated all activating receptors including NKG2D [84]. Recently, we showed that ex vivo NK cell exposure to a BETi compound, HMBA, reduced expression of NKG2D and its DAP10 adaptor molecule, impairing NKG2D-mediated cytotoxicity and dampening NK cell capacity to respond to IL-15 stimulation which is dependent on DAP10 [87]. Conversely, work performed by different groups including ours have shown that exposure to Prostratin results in overall activation of NK cells associated with upmodulation of NKG2D and NKp44 receptors, shedding of CD16, and, most importantly, in an enhanced NK cell-mediated clearance of T cells latently or productively infected with HIV-1 [25,84,85].…”

Section: Impact Of Lras On Nk Cell Phenotype and Functionmentioning

confidence: 99%

Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir

Desimio

Covino

Doria

2019

IJMS

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Viral persistency in latently infected CD4+ T cells despite antiretroviral therapy (ART) represents a major drawback in the fight against HIV-1. Efforts to purge latent HIV-1 have been attempted using latency reversing agents (LRAs) that activate expression of the quiescent virus. However, initial trials have shown that immune responses of ART-treated patients are ineffective at clearing LRA-reactivated HIV-1 reservoirs, suggesting that an adjuvant immunotherapy is needed. Here we overview multiple lines of evidence indicating that natural killer (NK) cells have the potential to induce anti-HIV-1 responses relevant for virus eradication. In particular, we focus on the role of the NKG2D activating receptor that crucially enables NK cell-mediated killing of HIV-1-infected cells. We describe recent data indicating that LRAs can synergize with HIV-1 at upregulating ligands for NKG2D (NKG2DLs), hence sensitizing T cells that exit from viral latency for recognition and lysis by NK cells; in addition, we report in vivo and ex vivo data showing the potential benefits and drawbacks that LRAs may have on NKG2D expression and, more in general, on the cytotoxicity of NK cells. Finally, we discuss how the NKG2D/NKG2DLs axis can be exploited for the development of effective HIV-1 eradication strategies combining LRA-induced virus reactivation with recently optimized NK cell-based immunotherapies.

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Hexamethylene bisacetamide impairs NK cell-mediated clearance of acute T lymphoblastic leukemia cells and HIV-1-infected T cells that exit viral latency

Cited by 9 publications

References 68 publications

DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?

DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?

A functional mammalian display screen identifies rare antibodies that stimulate NK cell–mediated cytotoxicity

Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir

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