Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

Bhat, Jaydeep; Dubin, Samuel; Dananberg, Alexandra; Quabius, Elgar Susanne; Fritsch, Jürgen; Dowds, C. Marie; Saxena, Ankit; Chitadze, Guranda; Lettau, Marcus; Kabelitz, Dieter

doi:10.3389/fimmu.2019.00569

Cited by 24 publications

(22 citation statements)

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“… 212 VPA was shown to synergize with ZOL in enhancing γδ T cell cytotoxicity at the level of pAg production 213 but also affected the interaction between γδ T cells and tumor cells at the level of the NKG2D receptor/ligand axis. 214 By contrast, decitabine increased the sensitivity of osteosarcoma cells to Vδ2 T cell killing by upregulating the cell surface expression of NKG2D ligands. 215 Overall, epigenetic drugs offer interesting perspectives for combination with γδ T cell immunotherapies.…”

Section: Combination Matters: How To Improve γδ T Cell Therapymentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

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Section: Combination Matters: How To Improve γδ T Cell Therapymentioning

confidence: 99%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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“…Current information about the impact of HDACis on γδ T cells is limited and comes from cancer studies using Valproic acid (Bhat et al, 2019), which was shown to be ineffective at reactivating persistent HIV in vivo (Archin et al, 2008). This cancer study showed a downregulation of the NKG2D receptor and redistribution of γδ T cell memory subsets (Bhat et al, 2019). Additional studies have focused on the effect of different LRAs on NK cell function showing mixed results.…”

Section: Effect Of Lras On Immune Cell Functionmentioning

confidence: 99%

Boosting the Immune System for HIV Cure: A γδ T Cell Perspective

Mann

Sambrano

Maggirwar

et al. 2020

Front. Cell. Infect. Microbiol.

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The major barrier to HIV cure is a population of long-lived cells that harbor latent but replication-competent virus, are not eliminated by antiretroviral therapy (ART), and remain indistinguishable from uninfected cells. However, ART does not cure HIV infection, side effects to treatment still occur, and the steady global rate of new infections makes finding a sustained ART-free HIV remission or cure for HIV-seropositive individuals urgently needed. Approaches aimed to cure HIV are mostly based on the "shock and kill" method that entails the use of a drug compound to reactivate latent virus paired together with strategies to boost or supplement the existing immune system to clear reactivated latently infected cells. Traditionally, these strategies have utilized CD8+ cytotoxic lymphocytes (CTL) but have been met with a number of challenges. Enhancing innate immune cell populations, such as γδ T cells, may provide an alternative route to HIV cure. γδ T cells possess anti-viral and cytotoxic capabilities that have been shown to directly inhibit HIV infection and specifically eliminate reactivated, latently infected cells in vitro. Most notably, their access to immune privileged anatomical sites and MHC-independent antigen recognition may circumvent many of the challenges facing CTL-based strategies. In this review, we discuss the role of γδ T cells in normal immunity and HIV infection as well as their current use in strategies to treat cancer. We present this information as means to speculate about the utilization of γδ T cells for HIV cure strategies and highlight some of the fundamental gaps in knowledge that require investigation.

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“…Some HDACi such as Trichostatin A (TSA), suberanilohydroxamic acid (SAHA or vorinostat), PXD101 (belinostat), LBH589 (panobinostat) and LAQ824 (dacinostat) are broad spectrum HDACi; others such as valproic acid (VPA), sodium butyrate (NaB), trapoxin and apicidin exhibit specificity for certain groups of HDAC; and others such as MS-275 (entinostat) and FR901228 (romidepsin, depsipeptide or FK228) exhibit high specificity for certain HDAC ( 248 , 249 ). HDACi exert antiproliferative effects through the induction of cell-cycle arrest, apoptosis, and autophagy, but it has been observed that TSA ( 247 , 250 – 253 ), SAHA ( 247 , 254 – 257 ), belinostat ( 247 ), VPA ( 246 , 251 , 252 , 254 , 258 – 270 ), NaB ( 251 , 252 , 255 , 257 , 258 , 261 , 271 ), romidepsin ( 247 ) and entinostat ( 255 , 257 , 269 ) trigger up-regulation of MICA/B in different cell lines derived from liquid and solid tumors. In most cases, it was demonstrated that HDACi induce upregulation of MICA/B accompanied by a higher NKG2D-dependent, NK cell-mediated cytotoxicity against HDACi-treated tumor cells ( 246 , 247 , 250 , 251 , 253 , 255 , 257 – 259 , 261 – 266 , 271 ).…”

Section: Rational Design Of Combination Therapies That Target the Nkg2d-nkg2dl Axismentioning

confidence: 99%

Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

Cited by 24 publications

References 50 publications

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cancer immunotherapy with γδ T cells: many paths ahead of us

Boosting the Immune System for HIV Cure: A γδ T Cell Perspective

Leveraging NKG2D Ligands in Immuno-Oncology

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