NKG2D/NKG2D Ligand System in Cancer: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by John Maher.

The family of human NKG2D ligands (NKG2DL) consists of eight stress-induced molecules. Over 80% of human cancers express these ligands on the surface of tumour cells and/or associated stromal elements. In mice, NKG2D deficiency increases susceptibility to some types of cancer, implicating this system in immune surveillance for malignancy. However, NKG2DL can also be shed, released via exosomes and trapped intracellularly, leading to immunosuppressive effects. Moreover, NKG2D can enhance chronic inflammatory processes which themselves can increase cancer risk and progression. Indeed, tumours commonly deploy a range of countermeasures that can neutralise or even corrupt this surveillance system, tipping the balance away from immune control towards tumour progression. Consequently, the prognostic impact of NKG2DL expression in human cancer is variable. 

  • cancer
  • NKG2D
  • NKG2D ligands
  • MICA/B
  • ULBP
  • Rae-1
  • H60
  • MULT1

1. Introduction

Natural killer group 2, member D (NKG2D), encoded by Klrk1, is an immune-activating receptor that belongs to the family of C-type lectin-like type II transmembrane proteins. It participates in both innate and adaptive immune responses and immune surveillance and is expressed on natural killer (NK) cells, invariant natural killer T (iNKT) cells, γδ T cells and CD8+ T cells [1]. CD4+ T cells do not generally express NKG2D, but its expression is inducible under pathological conditions, including rheumatoid arthritis [2] and cancer [3]. Like many other C-type lectin receptors, NKG2D engages multiple ligands (NKG2DL), which are induced by a range of cell stress events [4]. In humans, the NKG2DL family consists of two MHC class I-related polypeptides (MIC), namely, MICA and MICB, and six members of the UL16-binding protein (ULBP) family (1–6) [5]. However, the latter is something of a misnomer since only ULBP1 and -2, but not ULBP3–6, bind to the human cytomegalovirus (CMV) protein UL16 [6]. ULBP1–6 are also known as RAET1I, RAET1H, RAET1N, RAET1E, RAET1G and RAET1L, respectively, since they are counterparts of the mouse NKG2DL subfamily known as retinoic acid early inducible proteins (Rae—see below). All NKG2DL are distant MHC class I-like molecules which do not associate with β2 microglobulin. NKG2DL are highly polymorphic in humans (second only to MHC molecules in this respect), an attribute that affects their expression, affinity for NKG2D and disease susceptibility [7]. MICA, MICB and ULBP4 are expressed as membrane-spanning proteins, while ULBP1, ULBP3, ULBP6 and the allelic variant MICA*008 are anchored via a glycophosphatidylinositol (GPI) motif [8]. ULBP2 and ULBP5 can be expressed in either conformation [9]. Importantly, human NKG2D can discriminate between individual ligands in a manner that is enhanced by mechanical force, leading to significant variation in both signalling and functional outcomes within immune cells [10]. In the mouse, the NKG2DL family exhibits limited homology to the human system, comprising five Rae-1 family isoforms (a–e), three H60 isoforms (a–c) and Mult-1 [11].

2. NKG2D-Mediated Immune Response

The NKG2D system operates primarily in NK, CD8+ αβ T cells and γδ T cells. Although NK cell activation is controlled by the relative balance of inhibitory and activating signals, ligation of the NKG2D receptor by any NKG2DL is sufficient to trigger lytic synapse formation [16,17][12][13] and degranulation [18][14], overriding concomitant inhibitory cues [7]. NKG2D-triggered NK cell activation is further enhanced when the LFA-1 and 2B4 receptors interact with their respective ligands present on target cells [19][15]. Signalling via NKG2D can also enhance NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) [20][16], including that promoted by therapeutic monoclonal antibodies such as rituximab [21][17]. In advanced cancer, circulating numbers of NKG2D-expressing NK cells are commonly reduced [22[18][19],23], and the cells often have impaired cytotoxic activity [22,24][18][20]. Conversely, the presence of tumour-infiltrating NK cells is associated with improved outcomes in several cancer types, including breast cancer [25][21], gastric carcinoma [26][22] and neuroblastoma [27][23].
Unlike NK cells, CD8+ T cells cannot be activated fully by NKG2D ligation alone. Instead, NKG2D functions as a co-stimulatory molecule in these cells, facilitating enhanced cytokine release upon T cell receptor stimulation [28,29][24][25]. Although NKG2D is not normally expressed by CD4+ T cells, NKG2D+ CD4+ T cells can accumulate in cases of chronic inflammation or cancer [3]. In cancer, these cells demonstrate immunosuppressive properties mediated by soluble Fas ligands and other immunosuppressive cytokines [3].
γδ T cells constitute around 5% of all T cells. The dominant subtype found in blood expresses a Vγ9Vδ2 T cell receptor, and these cells can receive both activating (e.g., cytotoxicity-promoting) and co-stimulatory signals via NKG2D [30][26]. Tissue-resident γδ T cells of the δ1 subset also express NKG2D and undergo activation when exposed to NKG2DL [31][27]. Although MICA is one of the human NKG2DL, it is also directly recognised by the T cell receptor found on some δ1 γδ T cells [32,33][28][29]. Human γδ T cells of both δ1 and δ2 subtypes are commonly found in solid tumours, and their presence is generally associated with a more favourable prognosis [34,35][30][31].

3. Expression of NKG2DL in Healthy Tissues

NKG2DL are typically present at low levels under homeostatic conditions, except in gastrointestinal and glandular epithelia where they are constitutively expressed [36,37][32][33]. In this context, expression is predominantly intracellular [38,39][34][35] and may change upon exposure to gut flora [40][36]. ULBP5 (RAET1G) isoform 1 is also highly expressed intracellularly in the anterior pituitary gland [41][37]. ULBP1 has been found in B cells and monocytes [42][38], while MICA and ULBP3 are present in bone marrow stromal cells [43][39]. The activation of T cells or the cytokine-mediated stimulation of monocytes and dendritic cells may also promote NKG2DL upregulation [44][40].
The expression of NKG2DL is subject to multiple forms of control at the level of epigenetic regulation [45][41], transcription, alternative mRNA splicing, post-transcriptional regulation (e.g., by microRNAs [46][42]), regulation of subcellular location (e.g., cytoplasmic versus cell surface) and release of soluble forms, either by cleavage or in exosomes [7,47][7][43]. These regulatory pathways are considered in greater detail below. Tight regulation of NKG2DL expression is believed to be necessary in order to prevent autoimmunity [48][44]. Nonetheless, given this complexity, it is perhaps unsurprising that the expression of NKG2DL at the mRNA and protein levels does not always concur [39][35].

4. Induction and Regulation of NKG2DL Expression in Cancer

NKG2DL can be upregulated in response to a range of factors operating during malignant transformation. 
During the process of malignant transformation, DNA damage [71][45], activation of heat shock proteins [72][46] and oxidative stress [73][47] all occur. Remarkably, all of these factors stimulate NKG2DL expression, emphasizing the strong link between cancer and the presence of NKG2DL. In a seminal study, Gasser et al. demonstrated that the activation of the DNA damage response (DDR) triggers the production of NKG2DL [50][48]. The DDR is mediated by two key protein kinases—ataxia telangiectasia mutated (ATM) and ataxia telangiectasia RAD3-related (ATR)—and it is activated upon sensing double-stranded DNA breaks and stalled replication [74][49]. Importantly, this pathway is further amplified by radiotherapy and by multiple cytotoxic chemotherapy agents, including 5 fluorouracil, cisplatin, gemcitabine, temozolomide and vincristine [49,50,51,52,53,54,55][48][50][51][52][53][54][55]. The DDR also causes the activation of P53, which in turn stimulates the transcription of ULBP1 and ULBP2 but not MICA/B [75][56]. Another cytosolic DNA-sensing pathway, the stimulator of interferon genes (STING) pathway, was also shown to upregulate Rae-1 expression in mice [56][57]. Inhibition of the STING pathway decreased Rae-1 expression in lymphoma cells and reduced their sensitivity to NK-mediated lysis [57][58].
Several additional factors of potential relevance to cancer also upregulate NKG2DL expression. Early studies showed that promoter heat shock elements regulate MICA and MICB expression [36][32]; consequently, the abundance of these ligands is strongly enhanced in some settings by heat shock/cell stress [32][28]. Moreover, the ubiquitin-dependent degradation of the murine NKG2DL Mult-1 is reduced in response to heat shock or ultraviolet radiation, providing a precedent for the post-translational regulation of NKG2DL expression [76][59].
It is perhaps unsurprising that certain oncogenic pathways have also been implicated in the induction of NKG2DL expression. The activation of the BCR/ABL oncogenic pathway has been linked to increased NKG2DL expression in chronic myeloid leukaemia [63][60], while c-myc overexpression has been implicated in NKG2DL upregulation in both lymphoma [64][61] and AML [65][62]. Mutant ras can also promote the upregulation of NKG2DL in a manner that at least partially depends on PI3K [66][63].
Expression of MICA/B is also upregulated by oxidative stress [58,59][64][65] in an Erk-dependent manner [58][64], while p38 MAPK (mitogen-activated protein kinase) can also stimulate NKG2DL expression in some circumstances [55]. The combination of oxidative stress and Akt activation has recently been implicated in the ability of an antifungal agent (ciclopirox olamine) to increase NKG2DL expression by leukaemic cells [78][66].
Uncontrolled receptor signalling constitutes another cancer-associated process that increases NKG2DL expression. Illustrating this, the co-expression of the HER2/HER3 heterodimer resulted in the enhanced expression of MICA/B in breast cancer cell lines [67]. In both cases, PI3K signalling was implicated. Moreover, heightened EGF receptor activity has also been linked to NKG2DL upregulation [68].
A further broad stimulus to NKG2DL expression is cellular senescence [79][69], which is considered to be an emerging hallmark of cancer [80][70]. Adding complexity, senescent tumour cells may also increase NKG2DL shedding, favouring immune escape [81][71].
A number of transcription factors have been implicated in the regulation of NKG2DL expression. In the mouse, E2F transcription factors which promote cell cycle progression can direct the transcriptional upregulation of Rae-1 family members [60][72]. A similar process was inferred in the human system by virtue of reduced MICA/B and ULBP2 expression in serum-starved HCT116 cells [60][72]. It is also notable that E2F is a direct phosphorylation target of the ATM and ATR kinases mentioned above [44][40]. The KLF4 transcription factor also has been linked to the expression of MICA in acute myeloid leukaemia (AML) [61][73]. ULBP1 transcription is triggered by the ATF4 transcription factor, which is induced in response to nutrient deprivation, the unfolded protein response and oxidative stress [62][74]. However, MICA/B expression may be inhibited by the unfolded protein response under some circumstances, once again demonstrating the complex and context-dependent nature of NKG2DL regulation [82][75].
Metabolic rewiring is another distinctive feature of cancer [71][45]. Once again, NKG2DL expression is influenced by cancer-associated metabolic factors such as altered glycosylation [69,70][76][77].
Chronic inflammation is a key underpinning factor in the progression of many human cancers [83][78]. A number of inflammatory cytokines have been implicated in the control of NKG2DL expression. These include TNF-α and IL-18, both of which can upregulate ULBP2 levels in leukaemic cells [84][79]. NKG2DL are also upregulated by Toll-like receptor stimulation [85][80]. On the other hand, interferon (IFN)-γ has been shown to reduce NKG2DL on some tumour cell types, acting via STAT1 [86][81], microRNA induction [87][82] and MMP9 cleavage [88][83]. Similar inhibitory effects have been attributed to IFN-α [89][84], although there are also reports of NKG2DL upregulation in response to this cytokine [88][83]. Interleukin (IL)-6 and its downstream mediator, STAT3, have also been implicated in the downregulation of NKG2DL on tumour cells [90,91,92][85][86][87]. The effects of IL-10 on NKG2DL expression are complex: it downregulates MICA and upregulates MICB expression on melanoma cells [93][88] and increases NKG2DL levels on macrophages [94][89]. Transforming growth factor (TGF)-β downregulates the expression of NKG2DL on some tumour cell types [95,96][90][91]. Once again, however, this may not be a universal effect since the induction of tumour-associated epithelial-to-mesenchymal transition (EMT) by TGF-β may either upregulate [97][92] or downregulate [98][93] NKG2DL in a context-dependent manner.
Tumour cells can also influence NKG2DL expression on stromal cells. Illustrating this, the release of lactate dehydrogenase 5 by glioblastoma cells induces NKG2DL expression on monocytes which in turn causes NKG2D downregulation on NK cells [99][94]. Moreover, tumour-associated immune infiltrates and fibrovascular structures are commonly positive for NKG2DL, particularly the membrane of endothelial cells [100][95].
Despite the frequency with which NKG2DL are expressed in transformed cells, levels found in malignant stem cells may be reduced or absent [101,102][96][97]. In the case of AML stem cells, this reduction could be overcome using PARP (poly-ADP-ribose-polymerase 1) inhibitors [102][97]. Similarly, both ULBP1 and ULBP3 are repressed in glioma stem cells that contain mutations in isocitrate dehydrogenase (IDH) genes [103][98]. Nonetheless, other studies have confirmed that NKG2DL remain expressed on cancer stem cells in some settings (including glioma stem cells [104][99]) and contribute to their susceptibility to NK cell-mediated killing [105,106,107][100][101][102].
Finally, it should also be noted that NKG2D itself is also subject to cytokine-mediated regulation with increased expression in response to IL-2, IL-7, IL-12, IL-15 and type 1 interferons [108][103]. By contrast, the reduced expression of NKG2D has been linked to IL-21 and TGF-β exposure [108][103].

5. Tumour Evasion of NKG2D-Mediated Immune Surveillance

To counteract the above, cancers have evolved various mechanisms to evade NKG2D-dependent immune surveillance. Epigenetic repression of NKG2DL expression is mediated by several pathways, including histone deacetylation, enhancer of zeste homolog 2 and DNA methylation [109][104]. The cleavage of NKG2DL from the surfaces of tumour cells is also an important regulatory mechanism. Soluble NKG2DL are usually present at low levels in the circulation of healthy individuals. However, levels may be highly increased in cancer patients, reaching ng/mL concentrations on some occasions [110][105]. The release of soluble tumour-associated NKG2DL provides a potent mechanism to downregulate NKG2D on intratumoural CD8+ T cells and peripheral blood mononuclear cells (including NK cells) [111,112,113][106][107][108]. Elevated serum levels of soluble NKG2DL have been linked to worsened patient outcomes in several cancer types [114,115,116][109][110][111], although, in some cases, adverse prognosis is not directly linked to NKG2D downmodulation [117][112]. Moreover, patients who develop autoantibodies against MICA following anti-CTLA4 immunotherapy benefitted from a reduction in soluble MICA, restoration of NK and CD8+ T cell function and enhanced tumour lysis and dendritic cell cross-presentation [118][113].
There are two major pathways by which soluble NKG2DL are generated in cancer. First, NKG2DL undergo cleavage by ADAMs (a disintegrin and metalloproteinases) 10 and 17 and MMPs (matrix metalloproteinases), enzymes that are commonly increased in cancer [7,119,120][7][114][115]. NKG2DL may also be secreted within exosomes [7,121][7][116] or extracellular vesicles (EVs) that also contain pro-apoptotic molecules such as the TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) and the Fas ligand [122][117]. The relative contribution of cleaved and vesicle-derived soluble NKG2DL remains poorly characterized [123][118]. Membrane-spanning NKG2DL are primarily shed following proteolytic cleavage, while GPI-anchored NKG2DL mainly undergo release via EV. Nonetheless, both transmembrane- and GPI-anchored ligands may be found in EVs in various systems [9].
Intracellular retention of NKG2DL is another potential mechanism used to evade immune surveillance. MICA may be retained within the endoplasmic reticulum in some tumour types, in a manner that could be reversed using the proteasome inhibitor bortezomib [124][119]. Intracellular retention of NKG2DL may also be promoted by a number of CMV proteins [125][120] and by CEACAM1 [126][121].
A third recently described mechanism by which tumour cells can reduce MICA and MICB expression involves neddylation [127][122]. This entails the addition of a ubiquitin-like protein known as neuronal precursor cell-expressed developmentally downregulated protein (NEDD) 8, leading to protein degradation.
A further factor that can influence the outcome of the interaction between NKG2D and its ligands is trogocytosis, a process involving the acquisition of membrane and membrane proteins from other cells during cell-to-cell interactions. Both T cells [128][123] and NK cells [129][124] can trogocytose NKG2DL from other cell types, leading to varied outcomes including enhanced NK cell activation or failure of immune surveillance owing to the death of these cells via fratricide. More recently, the transfer of NKG2DL via EVs has been demonstrated in a multiple myeloma model. Once again, a double-edged outcome can be envisioned whereby cross-dressing of tumour cells may passively sensitise them to NKG2D-dependent elimination, but NKG2D downregulation and the sensitisation/fratricide of immune effector cells could thwart immune surveillance [9].

6. Role of the NKG2D/NKG2DL Axis in Animal Models of Cancer

As indicated above, the NKG2D/NKG2DL system is believed to play a critical role in the elimination of premalignant cells before they progress into clinically detectable tumours [130][125]. In agreement with this, when NKG2DL are expressed on a range of malignant cell types, they facilitate tumour rejection in vivo [131,132][126][127].
The role of NKG2D in tumour immune surveillance is strongly supported by the fact that NKG2D-deficient mice are more susceptible to spontaneous tumour development in the TRAMP (transgenic adenocarcinoma of mouse prostate) and Eµ-myc lymphoma transgenic model systems [133][128]. In the TRAMP model, but not in the Eµ-myc model, tumours arising in NKG2D-sufficient mice were depleted of NKG2DL when compared to those in NKG2D-deficient mice. This highlights a divergence in mechanisms by which NKG2D immune surveillance is bypassed in both models. Adding further complexity, although antibody-mediated NKG2D neutralisation promotes enhanced sarcoma formation in response to the chemical carcinogen 3-methylcholanthrene (3-MC) [134][129], NKG2D deficiency did not phenocopy this effect. Indeed, there was a small trend in the opposite direction in this more slowly evolving tumour type [133][128].
The maintained expression of NKG2DL is associated with a number of autoimmune and chronic inflammatory disease states, including rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, demyelinating conditions and coeliac disease [137][130]. It is noteworthy in this respect that chronic inflammation is a pathological process that can also facilitate malignant transformation [83][78]. Chronic activation of NKG2D can also accelerate tumourigenesis under some circumstances. Illustrating this, the sustained transgenic expression of an NKG2DL in vivo in a mouse model led to widespread NKG2D downregulation [138][131], reduced NK cell cytotoxicity mediated via NKG2D [139][132] and alternative receptor systems [140][133], sustained NK cell IFN-γ production [139][132] and enhanced susceptibility to chemically induced squamous cell carcinoma formation [138][131]. In a similar vein, the onset of diethylnitrosamine-induced hepatocellular carcinoma (HCC) was delayed in NKG2D-deficient mice [141][134].

7. Pharmacological Regulation of NKG2DL Expression

NKG2DL can be regulated by a wide spectrum of pharmacological agents. Upregulation of one or more ligands has been attributed to azacytidine, trichostatin A, vitamin D3, bryostatin, all-trans retinoic acid (ATRA), proteasome inhibitors, arsenic trioxide, multiple chemotherapy agents (see Section 4 above), decitabine, multitargeted tyrosine kinase inhibitors, inosine pranobex, nutlin-3a and histone deacetylase (HDAC) inhibitors such as sodium valproate and trichostatin A [51,52,54,55,103,143,144,145,146,147,148,149,150,151,152][51][52][54][55][98][135][136][137][138][139][140][141][142][143][144]. Mechanistically, HDAC inhibition leads to increased MICA expression at least in part via the transcription factor KLF4 [61][73]. Clinically relevant NKG2DL upregulation on malignant cells has been demonstrated in patients with AML following treatment with ATRA or valproic acid-containing chemotherapy regimens [153][145]. Moreover, in patients with pancreatic cancer who received neoadjuvant gemcitabine, MICA was expressed on 85% of tumours, in contrast to 36% of cases in the placebo-treated control group [154][146]. Gemcitabine also has the additional ability to reduce levels of soluble ULBP2 released by pancreatic cancer cell lines [155][147].
A further approach that may be used to increase the tumour cell surface expression of NKG2DL involves the inhibition of shedding of these ligands. Illustrating this, antibodies targeted against the α3 domain of MICA hindered the shedding of this ligand in addition to MICB [156][148]. As a result, NK-mediated anti-tumour activity was boosted in a number of tumour model systems. Alternatively, degradation of MICA and MICB may be inhibited using pharmacological inhibitors of neddylation [127][122]. Furthermore, as indicated above, the expression of NKG2DL on AML stem cells could be achieved using PARP inhibition [102][97].
By contrast, NKG2DL may also be downregulated using pharmacological interventions. Proteasome upregulation has been linked with the downregulated expression of ULBP1 [157][149]. Estradiol has been reported to either suppress [158][150] or stimulate NKG2DL expression [159][151] accompanied by enhanced ADAM 17-mediated cleavage [160][152]. Activation of the unfolded protein response in hepatocellular carcinoma cells also reduced the expression of MICA/B in a manner that was partially alleviated using proteasome inhibition [161][153]. Downregulation of NKG2DL in breast cancer cell lines has also been attributed to the anaesthetic agent sevoflurane [162][154]. Inhibition of BRAF with vemurafenib led to reduced MICA and ULBP2 expression by melanoma cells [163][155]. Rapamycin has also been linked to NKG2DL downregulation in AML [164][156]. Finally, the commonly used uricosuric agent allopurinol inhibited the upregulated expression of NKG2DL induced by genotoxic stress in a manner that was dependent on the inhibition of xanthine oxidoreductase [165][157]. In keeping with this, uric acid generated as a consequence of DNA damage and purine catabolism promoted MICA/B expression [166][158].

References

  1. Lanier, L.L. NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunol. Res. 2015, 3, 575–582.
  2. Groh, V.; Bruhl, A.; El-Gabalawy, H.; Nelson, J.L.; Spies, T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 2003, 100, 9452–9457.
  3. Groh, V.; Smythe, K.; Dai, Z.; Spies, T. Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity. Nat. Immunol. 2006, 7, 755–762.
  4. Brown, G.D.; Willment, J.A.; Whitehead, L. C-type lectins in immunity and homeostasis. Nat. Rev. Immunol. 2018, 18, 374–389.
  5. Wensveen, F.M.; Jelencic, V.; Polic, B. NKG2D: A Master Regulator of Immune Cell Responsiveness. Front. Immunol. 2018, 9, 441.
  6. Cosman, D.; Mullberg, J.; Sutherland, C.L.; Chin, W.; Armitage, R.; Fanslow, W.; Kubin, M.; Chalupny, N.J. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 2001, 14, 123–133.
  7. Zingoni, A.; Molfetta, R.; Fionda, C.; Soriani, A.; Paolini, R.; Cippitelli, M.; Cerboni, C.; Santoni, A. NKG2D and Its Ligands: “One for All, All for One”. Front. Immunol. 2018, 9, 476.
  8. Ashiru, O.; Lopez-Cobo, S.; Fernandez-Messina, L.; Pontes-Quero, S.; Pandolfi, R.; Reyburn, H.T.; Vales-Gomez, M. A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008. Biochem. J. 2013, 454, 295–302.
  9. Vulpis, E.; Loconte, L.; Cassone, C.; Antonangeli, F.; Caracciolo, G.; Masuelli, L.; Fazio, F.; Petrucci, M.T.; Fionda, C.; Soriani, A.; et al. Cross-Dressing of Multiple Myeloma Cells Mediated by Extracellular Vesicles Conveying MIC and ULBP Ligands Promotes NK Cell Killing. Int. J. Mol. Sci. 2023, 24, 9467.
  10. Fan, J.; Shi, J.; Zhang, Y.; Liu, J.; An, C.; Zhu, H.; Wu, P.; Hu, W.; Qin, R.; Yao, D.; et al. NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes. EMBO J. 2022, 41, e107739.
  11. Duan, S.; Guo, W.; Xu, Z.; He, Y.; Liang, C.; Mo, Y.; Wang, Y.; Xiong, F.; Guo, C.; Li, Y.; et al. Natural killer group 2D receptor and its ligands in cancer immune escape. Mol. Cancer 2019, 18, 29.
  12. Wilton, K.M.; Overlee, B.L.; Billadeau, D.D. NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity. J. Cell Sci. 2019, 133, jcs230508.
  13. Brown, A.C.; Dobbie, I.M.; Alakoskela, J.M.; Davis, I.; Davis, D.M. Super-resolution imaging of remodeled synaptic actin reveals different synergies between NK cell receptors and integrins. Blood 2012, 120, 3729–3740.
  14. Bauer, S.; Groh, V.; Wu, J.; Steinle, A.; Phillips, J.H.; Lanier, L.L.; Spies, T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999, 285, 727–729.
  15. Bryceson, Y.T.; Ljunggren, H.G.; Long, E.O. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 2009, 114, 2657–2666.
  16. Parsons, M.S.; Richard, J.; Lee, W.S.; Vanderven, H.; Grant, M.D.; Finzi, A.; Kent, S.J. NKG2D Acts as a Co-Receptor for Natural Killer Cell-Mediated Anti-HIV-1 Antibody-Dependent Cellular Cytotoxicity. AIDS Res. Hum. Retrovir. 2016, 32, 1089–1096.
  17. Inagaki, A.; Ishida, T.; Yano, H.; Ishii, T.; Kusumoto, S.; Ito, A.; Ri, M.; Mori, F.; Ding, J.; Komatsu, H.; et al. Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC. Int. J. Cancer 2009, 125, 212–221.
  18. Shen, Y.; Lu, C.; Tian, W.; Wang, L.; Cui, B.; Jiao, Y.; Ma, C.; Ju, Y.; Zhu, L.; Shao, C.; et al. Possible association of decreased NKG2D expression levels and suppression of the activity of natural killer cells in patients with colorectal cancer. Int. J. Oncol. 2012, 40, 1285–1290.
  19. Secchiari, F.; Nunez, S.Y.; Sierra, J.M.; Ziblat, A.; Regge, M.V.; Raffo Iraolagoitia, X.L.; Rovegno, A.; Ameri, C.; Secin, F.P.; Richards, N.; et al. The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology. Oncoimmunology 2022, 11, 2104991.
  20. Doubrovina, E.S.; Doubrovin, M.M.; Vider, E.; Sisson, R.B.; O’Reilly, R.J.; Dupont, B.; Vyas, Y.M. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J. Immunol. 2003, 171, 6891–6899.
  21. Denkert, C.; von Minckwitz, G.; Darb-Esfahani, S.; Lederer, B.; Heppner, B.I.; Weber, K.E.; Budczies, J.; Huober, J.; Klauschen, F.; Furlanetto, J.; et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018, 19, 40–50.
  22. Pernot, S.; Terme, M.; Radosevic-Robin, N.; Castan, F.; Badoual, C.; Marcheteau, E.; Penault-Llorca, F.; Bouche, O.; Bennouna, J.; Francois, E.; et al. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance. Gastric Cancer 2020, 23, 73–81.
  23. Semeraro, M.; Rusakiewicz, S.; Minard-Colin, V.; Delahaye, N.F.; Enot, D.; Vely, F.; Marabelle, A.; Papoular, B.; Piperoglou, C.; Ponzoni, M.; et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci. Transl. Med. 2015, 7, 283ra255.
  24. Maasho, K.; Opoku-Anane, J.; Marusina, A.I.; Coligan, J.E.; Borrego, F. NKG2D is a costimulatory receptor for human naive CD8+ T cells. J. Immunol. 2005, 174, 4480–4484.
  25. Groh, V.; Rhinehart, R.; Randolph-Habecker, J.; Topp, M.S.; Riddell, S.R.; Spies, T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat. Immunol. 2001, 2, 255–260.
  26. Rincon-Orozco, B.; Kunzmann, V.; Wrobel, P.; Kabelitz, D.; Steinle, A.; Herrmann, T. Activation of V gamma 9V delta 2 T cells by NKG2D. J. Immunol. 2005, 175, 2144–2151.
  27. Wu, Y.; Kyle-Cezar, F.; Woolf, R.T.; Naceur-Lombardelli, C.; Owen, J.; Biswas, D.; Lorenc, A.; Vantourout, P.; Gazinska, P.; Grigoriadis, A.; et al. An innate-like Vdelta1(+) gammadelta T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci. Transl. Med. 2019, 11, eaax9364.
  28. Groh, V.; Steinle, A.; Bauer, S.; Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science 1998, 279, 1737–1740.
  29. Wu, J.; Groh, V.; Spies, T. T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells. J. Immunol. 2002, 169, 1236–1240.
  30. Gentles, A.J.; Newman, A.M.; Liu, C.L.; Bratman, S.V.; Feng, W.; Kim, D.; Nair, V.S.; Xu, Y.; Khuong, A.; Hoang, C.D.; et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 2015, 21, 938–945.
  31. Tosolini, M.; Pont, F.; Poupot, M.; Vergez, F.; Nicolau-Travers, M.L.; Vermijlen, D.; Sarry, J.E.; Dieli, F.; Fournie, J.J. Assessment of tumor-infiltrating TCRVgamma9Vdelta2 gammadelta lymphocyte abundance by deconvolution of human cancers microarrays. Oncoimmunology 2017, 6, e1284723.
  32. Groh, V.; Bahram, S.; Bauer, S.; Herman, A.; Beauchamp, M.; Spies, T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. USA 1996, 93, 12445–12450.
  33. Ghadially, H.; Brown, L.; Lloyd, C.; Lewis, L.; Lewis, A.; Dillon, J.; Sainson, R.; Jovanovic, J.; Tigue, N.J.; Bannister, D.; et al. MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue. Br. J. Cancer 2017, 116, 1208–1217.
  34. Hue, S.; Mention, J.J.; Monteiro, R.C.; Zhang, S.; Cellier, C.; Schmitz, J.; Verkarre, V.; Fodil, N.; Bahram, S.; Cerf-Bensussan, N.; et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004, 21, 367–377.
  35. Eagle, R.A.; Jafferji, I.; Barrow, A.D. Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells. Curr. Immunol. Rev. 2009, 5, 22–34.
  36. Hansen, C.H.; Holm, T.L.; Krych, L.; Andresen, L.; Nielsen, D.S.; Rune, I.; Hansen, A.K.; Skov, S. Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells. Eur. J. Immunol. 2013, 43, 447–457.
  37. Eagle, R.A.; Flack, G.; Warford, A.; Martinez-Borra, J.; Jafferji, I.; Traherne, J.A.; Ohashi, M.; Boyle, L.H.; Barrow, A.D.; Caillat-Zucman, S.; et al. Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G. PLoS ONE 2009, 4, e4503.
  38. Nowbakht, P.; Ionescu, M.C.; Rohner, A.; Kalberer, C.P.; Rossy, E.; Mori, L.; Cosman, D.; De Libero, G.; Wodnar-Filipowicz, A. Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 2005, 105, 3615–3622.
  39. Poggi, A.; Prevosto, C.; Massaro, A.M.; Negrini, S.; Urbani, S.; Pierri, I.; Saccardi, R.; Gobbi, M.; Zocchi, M.R. Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: Role of NKp30 and NKG2D receptors. J. Immunol. 2005, 175, 6352–6360.
  40. Jones, A.B.; Rocco, A.; Lamb, L.S.; Friedman, G.K.; Hjelmeland, A.B. Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression. Cancers 2022, 14, 2339.
  41. Baragano Raneros, A.; Martin-Palanco, V.; Fernandez, A.F.; Rodriguez, R.M.; Fraga, M.F.; Lopez-Larrea, C.; Suarez-Alvarez, B. Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia. Genes Immun. 2015, 16, 71–82.
  42. Heinemann, A.; Zhao, F.; Pechlivanis, S.; Eberle, J.; Steinle, A.; Diederichs, S.; Schadendorf, D.; Paschen, A. Tumor suppressive microRNAs miR-34a/c control cancer cell expression of ULBP2, a stress-induced ligand of the natural killer cell receptor NKG2D. Cancer Res. 2012, 72, 460–471.
  43. Stern-Ginossar, N.; Gur, C.; Biton, M.; Horwitz, E.; Elboim, M.; Stanietsky, N.; Mandelboim, M.; Mandelboim, O. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat. Immunol. 2008, 9, 1065–1073.
  44. Guerra, N.; Lanier, L.L. Editorial: Emerging Concepts on the NKG2D Receptor-Ligand Axis in Health and Diseases. Front. Immunol. 2020, 11, 562.
  45. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  46. Lang, B.J.; Guerrero-Gimenez, M.E.; Prince, T.L.; Ackerman, A.; Bonorino, C.; Calderwood, S.K. Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond. Int. J. Mol. Sci. 2019, 20, 4507.
  47. Hayes, J.D.; Dinkova-Kostova, A.T.; Tew, K.D. Oxidative Stress in Cancer. Cancer Cell 2020, 38, 167–197.
  48. Gasser, S.; Orsulic, S.; Brown, E.J.; Raulet, D.H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005, 436, 1186–1190.
  49. Williams, R.M.; Zhang, X. Roles of ATM and ATR in DNA double strand breaks and replication stress. Prog. Biophys. Mol. Biol. 2021, 163, 109–119.
  50. Kim, J.Y.; Son, Y.O.; Park, S.W.; Bae, J.H.; Chung, J.S.; Kim, H.H.; Chung, B.S.; Kim, S.H.; Kang, C.D. Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp. Mol. Med. 2006, 38, 474–484.
  51. Weiss, T.; Schneider, H.; Silginer, M.; Steinle, A.; Pruschy, M.; Polic, B.; Weller, M.; Roth, P. NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma. Clin. Cancer Res. 2018, 24, 882–895.
  52. Zhao, L.; Wang, W.J.; Zhang, J.N.; Zhang, X.Y. 5-Fluorouracil and interleukin-2 immunochemotherapy enhances immunogenicity of non-small cell lung cancer A549 cells through upregulation of NKG2D ligands. Asian Pac. J. Cancer Prev. 2014, 15, 4039–4044.
  53. Soriani, A.; Zingoni, A.; Cerboni, C.; Iannitto, M.L.; Ricciardi, M.R.; Di Gialleonardo, V.; Cippitelli, M.; Fionda, C.; Petrucci, M.T.; Guarini, A.; et al. ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 2009, 113, 3503–3511.
  54. Okita, R.; Wolf, D.; Yasuda, K.; Maeda, A.; Yukawa, T.; Saisho, S.; Shimizu, K.; Yamaguchi, Y.; Oka, M.; Nakayama, E.; et al. Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells. PLoS ONE 2015, 10, e0139809.
  55. Soriani, A.; Borrelli, C.; Ricci, B.; Molfetta, R.; Zingoni, A.; Fionda, C.; Carnevale, S.; Abruzzese, M.P.; Petrucci, M.T.; Ricciardi, M.R.; et al. p38 MAPK differentially controls NK activating ligands at transcriptional and post-transcriptional level on multiple myeloma cells. Oncoimmunology 2017, 6, e1264564.
  56. Textor, S.; Fiegler, N.; Arnold, A.; Porgador, A.; Hofmann, T.G.; Cerwenka, A. Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res. 2011, 71, 5998–6009.
  57. Le Bert, N.; Lam, A.R.; Ho, S.S.; Shen, Y.J.; Liu, M.M.; Gasser, S. STING-dependent cytosolic DNA sensor pathways regulate NKG2D ligand expression. Oncoimmunology 2014, 3, e29259.
  58. Lam, A.R.; Bert, N.L.; Ho, S.S.; Shen, Y.J.; Tang, L.F.; Xiong, G.M.; Croxford, J.L.; Koo, C.X.; Ishii, K.J.; Akira, S.; et al. RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer Res. 2014, 74, 2193–2203.
  59. Nice, T.J.; Coscoy, L.; Raulet, D.H. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. J. Exp. Med. 2009, 206, 287–298.
  60. Boissel, N.; Rea, D.; Tieng, V.; Dulphy, N.; Brun, M.; Cayuela, J.M.; Rousselot, P.; Tamouza, R.; Le Bouteiller, P.; Mahon, F.X.; et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J. Immunol. 2006, 176, 5108–5116.
  61. Unni, A.M.; Bondar, T.; Medzhitov, R. Intrinsic sensor of oncogenic transformation induces a signal for innate immunosurveillance. Proc. Natl. Acad. Sci. USA 2008, 105, 1686–1691.
  62. Nanbakhsh, A.; Pochon, C.; Mallavialle, A.; Amsellem, S.; Bourhis, J.H.; Chouaib, S. c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis. Blood 2014, 123, 3585–3595.
  63. Liu, X.V.; Ho, S.S.; Tan, J.J.; Kamran, N.; Gasser, S. Ras activation induces expression of Raet1 family NK receptor ligands. J. Immunol. 2012, 189, 1826–1834.
  64. Borchers, M.T.; Harris, N.L.; Wesselkamper, S.C.; Vitucci, M.; Cosman, D. NKG2D ligands are expressed on stressed human airway epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006, 291, L222–L231.
  65. Yamamoto, K.; Fujiyama, Y.; Andoh, A.; Bamba, T.; Okabe, H. Oxidative stress increases MICA and MICB gene expression in the human colon carcinoma cell line (CaCO2). Biochim. Biophys. Acta 2001, 1526, 10–12.
  66. Zhu, Y.; Zhao, Z.; Xue, M.; Wang, D.; Su, G.; Ju, X.; Yang, Q.; Zhang, S.; Fan, D.; Zhu, H.; et al. Ciclopirox olamine sensitizes leukemia cells to natural killer cell-mediated cytolysis by upregulating NKG2DLs via the Akt signaling pathway. Biochem. Biophys. Res. Commun. 2023, 659, 10–19.
  67. Okita, R.; Mougiakakos, D.; Ando, T.; Mao, Y.; Sarhan, D.; Wennerberg, E.; Seliger, B.; Lundqvist, A.; Mimura, K.; Kiessling, R. HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines. J. Immunol. 2012, 188, 2136–2145.
  68. Vantourout, P.; Willcox, C.; Turner, A.; Swanson, C.M.; Haque, Y.; Sobolev, O.; Grigoriadis, A.; Tutt, A.; Hayday, A. Immunological visibility: Posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci. Transl. Med. 2014, 6, 231ra249.
  69. Sagiv, A.; Burton, D.G.; Moshayev, Z.; Vadai, E.; Wensveen, F.; Ben-Dor, S.; Golani, O.; Polic, B.; Krizhanovsky, V. NKG2D ligands mediate immunosurveillance of senescent cells. Aging 2016, 8, 328–344.
  70. Domen, A.; Deben, C.; Verswyvel, J.; Flieswasser, T.; Prenen, H.; Peeters, M.; Lardon, F.; Wouters, A. Cellular senescence in cancer: Clinical detection and prognostic implications. J. Exp. Clin. Cancer Res. 2022, 41, 360.
  71. Zhang, Y.; Hu, R.; Xi, B.; Nie, D.; Xu, H.; Liu, A. Mechanisms of Senescence-Related NKG2D Ligands Release and Immune Escape Induced by Chemotherapy in Neuroblastoma Cells. Front. Cell Dev. Biol. 2022, 10, 829404.
  72. Jung, H.; Hsiung, B.; Pestal, K.; Procyk, E.; Raulet, D.H. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J. Exp. Med. 2012, 209, 2409–2422.
  73. Alkhayer, R.; Ponath, V.; Frech, M.; Adhikary, T.; Graumann, J.; Neubauer, A.; von Strandmann, E.P. KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: A novel therapeutic target identified by enChIP. Cell Commun. Signal. 2023, 21, 94.
  74. Gowen, B.G.; Chim, B.; Marceau, C.D.; Greene, T.T.; Burr, P.; Gonzalez, J.R.; Hesser, C.R.; Dietzen, P.A.; Russell, T.; Iannello, A.; et al. A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells. Elife 2015, 4, e08474.
  75. Obiedat, A.; Seidel, E.; Mahameed, M.; Berhani, O.; Tsukerman, P.; Voutetakis, K.; Chatziioannou, A.; McMahon, M.; Avril, T.; Chevet, E.; et al. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1. FASEB J. 2019, 33, 3481–3495.
  76. Andresen, L.; Skovbakke, S.L.; Persson, G.; Hagemann-Jensen, M.; Hansen, K.A.; Jensen, H.; Skov, S. 2-deoxy D-glucose prevents cell surface expression of NKG2D ligands through inhibition of N-linked glycosylation. J. Immunol. 2012, 188, 1847–1855.
  77. Moller, S.H.; Mellergaard, M.; Madsen, M.; Bermejo, A.V.; Jepsen, S.D.; Hansen, M.H.; Hogh, R.I.; Aldana, B.I.; Desler, C.; Rasmussen, L.J.; et al. Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells. Front. Immunol. 2020, 11, 1968.
  78. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867.
  79. Song, H.; Kim, K.E.; Hur, D.; Lim, J.S.; Yang, Y.; Cho, B.J.; Kim, C.H.; Kim, T.; Bang, S.; Lee, W.J.; et al. IL-18 enhances ULBP2 expression through the MAPK pathway in leukemia cells. Immunol. Lett. 2008, 120, 103–107.
  80. Hamerman, J.A.; Ogasawara, K.; Lanier, L.L. Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J. Immunol. 2004, 172, 2001–2005.
  81. Schwinn, N.; Vokhminova, D.; Sucker, A.; Textor, S.; Striegel, S.; Moll, I.; Nausch, N.; Tuettenberg, J.; Steinle, A.; Cerwenka, A.; et al. Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells. Int. J. Cancer 2009, 124, 1594–1604.
  82. Yadav, D.; Ngolab, J.; Lim, R.S.; Krishnamurthy, S.; Bui, J.D. Cutting edge: Down-regulation of MHC class I-related chain A on tumor cells by IFN-gamma-induced microRNA. J. Immunol. 2009, 182, 39–43.
  83. Zhang, C.; Niu, J.; Zhang, J.; Wang, Y.; Zhou, Z.; Zhang, J.; Tian, Z. Opposing effects of interferon-alpha and interferon-gamma on the expression of major histocompatibility complex class I chain-related A in tumors. Cancer Sci. 2008, 99, 1279–1286.
  84. Bui, J.D.; Carayannopoulos, L.N.; Lanier, L.L.; Yokoyama, W.M.; Schreiber, R.D. IFN-dependent down-regulation of the NKG2D ligand H60 on tumors. J. Immunol. 2006, 176, 905–913.
  85. Bedel, R.; Thiery-Vuillemin, A.; Grandclement, C.; Balland, J.; Remy-Martin, J.P.; Kantelip, B.; Pallandre, J.R.; Pivot, X.; Ferrand, C.; Tiberghien, P.; et al. Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. Cancer Res. 2011, 71, 1615–1626.
  86. Cai, X.; Lu, X.; Jia, Z.; Zhang, X.; Han, W.; Rong, X.; Ma, L.; Zhou, M.; Chen, B. STAT3 contributes to NK cell recognition by modulating expression of NKG2D ligands in adriamycin-resistant K562/AO2 cells. Int. J. Hematol. 2015, 102, 536–543.
  87. Xu, L.; Chen, X.; Shen, M.; Yang, D.R.; Fang, L.; Weng, G.; Tsai, Y.; Keng, P.C.; Chen, Y.; Lee, S.O. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol. Oncol. 2018, 12, 269–286.
  88. Serrano, A.E.; Menares-Castillo, E.; Garrido-Tapia, M.; Ribeiro, C.H.; Hernandez, C.J.; Mendoza-Naranjo, A.; Gatica-Andrades, M.; Valenzuela-Diaz, R.; Zuniga, R.; Lopez, M.N.; et al. Interleukin 10 decreases MICA expression on melanoma cell surface. Immunol. Cell Biol. 2011, 89, 447–457.
  89. Schulz, U.; Kreutz, M.; Multhoff, G.; Stoelcker, B.; Kohler, M.; Andreesen, R.; Holler, E. Interleukin-10 promotes NK cell killing of autologous macrophages by stimulating expression of NKG2D ligands. Scand. J. Immunol. 2010, 72, 319–331.
  90. Eisele, G.; Wischhusen, J.; Mittelbronn, M.; Meyermann, R.; Waldhauer, I.; Steinle, A.; Weller, M.; Friese, M.A. TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 2006, 129, 2416–2425.
  91. Trinh, T.L.; Kandell, W.M.; Donatelli, S.S.; Tu, N.; Tejera, M.M.; Gilvary, D.L.; Eksioglu, E.A.; Burnette, A.; Adams, W.A.; Liu, J.; et al. Immune evasion by TGFbeta-induced miR-183 repression of MICA/B expression in human lung tumor cells. Oncoimmunology 2019, 8, e1557372.
  92. Lopez-Soto, A.; Huergo-Zapico, L.; Galvan, J.A.; Rodrigo, L.; de Herreros, A.G.; Astudillo, A.; Gonzalez, S. Epithelial-mesenchymal transition induces an antitumor immune response mediated by NKG2D receptor. J. Immunol. 2013, 190, 4408–4419.
  93. Hu, B.; Tian, X.; Li, Y.; Liu, Y.; Yang, T.; Han, Z.; An, J.; Kong, L.; Li, Y. Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer Med. 2020, 9, 2686–2697.
  94. Crane, C.A.; Austgen, K.; Haberthur, K.; Hofmann, C.; Moyes, K.W.; Avanesyan, L.; Fong, L.; Campbell, M.J.; Cooper, S.; Oakes, S.A.; et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc. Natl. Acad. Sci. USA 2014, 111, 12823–12828.
  95. Agaugue, S.; Hargreaves, A.; Gilham, D.E. The high expression of NKG2D ligands on tumor and non-tumor cells and a lack of surface expression on healthy tissues provide a strong rationale to support NKG2D-based therapeutic approaches for cancer. Ann. Oncol. 2019, 29. Abstract 1179P (Poster presentation).
  96. Wang, B.; Wang, Q.; Wang, Z.; Jiang, J.; Yu, S.C.; Ping, Y.F.; Yang, J.; Xu, S.L.; Ye, X.Z.; Xu, C.; et al. Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells. Cancer Res. 2014, 74, 5746–5757.
  97. Paczulla, A.M.; Rothfelder, K.; Raffel, S.; Konantz, M.; Steinbacher, J.; Wang, H.; Tandler, C.; Mbarga, M.; Schaefer, T.; Falcone, M.; et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 2019, 572, 254–259.
  98. Zhang, X.; Rao, A.; Sette, P.; Deibert, C.; Pomerantz, A.; Kim, W.J.; Kohanbash, G.; Chang, Y.; Park, Y.; Engh, J.; et al. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro-Oncology 2016, 18, 1402–1412.
  99. Fluh, C.; Chitadze, G.; Adamski, V.; Hattermann, K.; Synowitz, M.; Kabelitz, D.; Held-Feindt, J. NKG2D ligands in glioma stem-like cells: Expression in situ and in vitro. Histochem. Cell Biol. 2018, 149, 219–233.
  100. Ames, E.; Canter, R.J.; Grossenbacher, S.K.; Mac, S.; Chen, M.; Smith, R.C.; Hagino, T.; Perez-Cunningham, J.; Sckisel, G.D.; Urayama, S.; et al. NK Cells Preferentially Target Tumor Cells with a Cancer Stem Cell Phenotype. J. Immunol. 2015, 195, 4010–4019.
  101. Yin, T.; Wang, G.; He, S.; Liu, Q.; Sun, J.; Wang, Y. Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells. Cell. Immunol. 2016, 300, 41–45.
  102. Oh, S.J.; Yang, J.I.; Kim, O.; Ahn, E.J.; Kang, W.D.; Lee, J.H.; Moon, K.S.; Lee, K.H.; Cho, D. Human U87 glioblastoma cells with stemness features display enhanced sensitivity to natural killer cell cytotoxicity through altered expression of NKG2D ligand. Cancer Cell Int. 2017, 17, 22.
  103. Zhang, J.; Basher, F.; Wu, J.D. NKG2D Ligands in Tumor Immunity: Two Sides of a Coin. Front. Immunol. 2015, 6, 97.
  104. Morimoto, Y.; Yamashita, N.; Daimon, T.; Hirose, H.; Yamano, S.; Haratake, N.; Ishikawa, S.; Bhattacharya, A.; Fushimi, A.; Ahmad, R.; et al. MUC1-C is a master regulator of MICA/B NKG2D ligand and exosome secretion in human cancer cells. J. Immunother. Cancer 2023, 11, e006238.
  105. Xing, S.; Ferrari de Andrade, L. NKG2D and MICA/B shedding: A ‘tag game’ between NK cells and malignant cells. Clin. Transl. Immunol. 2020, 9, e1230.
  106. Groh, V.; Wu, J.; Yee, C.; Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002, 419, 734–738.
  107. Chitadze, G.; Kabelitz, D. Immune surveillance in glioblastoma: Role of the NKG2D system and novel cell-based therapeutic approaches. Scand. J. Immunol. 2022, 96, e13201.
  108. Zhang, Y.; Luo, F.; Dong, K. Soluble NKG2D ligands impair CD8(+) T cell antitumor function dependent of NKG2D downregulation in neuroblastoma. Oncol. Lett. 2023, 26, 297.
  109. Li, J.J.; Pan, K.; Gu, M.F.; Chen, M.S.; Zhao, J.J.; Wang, H.; Liang, X.T.; Sun, J.C.; Xia, J.C. Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma. Chin. J. Cancer 2013, 32, 141–148.
  110. Kegasawa, T.; Tatsumi, T.; Yoshioka, T.; Suda, T.; Ikezawa, K.; Nakabori, T.; Yamada, R.; Kodama, T.; Shigekawa, M.; Hikita, H.; et al. Soluble UL16-binding protein 2 is associated with a poor prognosis in pancreatic cancer patients. Biochem. Biophys. Res. Commun. 2019, 517, 84–88.
  111. Chen, J.; Xu, H.; Zhu, X.X. Abnormal expression levels of sMICA and NKG2D are correlated with poor prognosis in pancreatic cancer. Ther. Clin. Risk Manag. 2016, 12, 11–18.
  112. Vyas, M.; Reinartz, S.; Hoffmann, N.; Reiners, K.S.; Lieber, S.; Jansen, J.M.; Wagner, U.; Muller, R.; von Strandmann, E.P. Soluble NKG2D ligands in the ovarian cancer microenvironment are associated with an adverse clinical outcome and decreased memory effector T cells independent of NKG2D downregulation. Oncoimmunology 2017, 6, e1339854.
  113. Jinushi, M.; Hodi, F.S.; Dranoff, G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA 2006, 103, 9190–9195.
  114. Salih, H.R.; Rammensee, H.G.; Steinle, A. Cutting edge: Down-regulation of MICA on human tumors by proteolytic shedding. J. Immunol. 2002, 169, 4098–4102.
  115. Chitadze, G.; Lettau, M.; Bhat, J.; Wesch, D.; Steinle, A.; Furst, D.; Mytilineos, J.; Kalthoff, H.; Janssen, O.; Oberg, H.H.; et al. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: Heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17. Int. J. Cancer 2013, 133, 1557–1566.
  116. Fernandez-Messina, L.; Ashiru, O.; Boutet, P.; Aguera-Gonzalez, S.; Skepper, J.N.; Reyburn, H.T.; Vales-Gomez, M. Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands. J. Biol. Chem. 2010, 285, 8543–8551.
  117. Bernareggi, D.; Xie, Q.; Prager, B.C.; Yun, J.; Cruz, L.S.; Pham, T.V.; Kim, W.; Lee, X.; Coffey, M.; Zalfa, C.; et al. CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity. Nat. Commun. 2022, 13, 1899.
  118. Campos-Silva, C.; Lopez-Borrego, S.; Felgueres, M.J.; Esteso, G.; Vales-Gomez, M. NKG2D Ligands in Liquid Biopsy: The Importance of Soluble and Vesicle-Bound Proteins for Immune Modulation. Crit. Rev. Immunol. 2022, 42, 21–40.
  119. Fuertes, M.B.; Girart, M.V.; Molinero, L.L.; Domaica, C.I.; Rossi, L.E.; Barrio, M.M.; Mordoh, J.; Rabinovich, G.A.; Zwirner, N.W. Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. J. Immunol. 2008, 180, 4606–4614.
  120. Champsaur, M.; Lanier, L.L. Effect of NKG2D ligand expression on host immune responses. Immunol. Rev. 2010, 235, 267–285.
  121. Chen, Z.; Chen, L.; Baker, K.; Olszak, T.; Zeissig, S.; Huang, Y.H.; Kuo, T.T.; Mandelboim, O.; Beauchemin, N.; Lanier, L.L.; et al. CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells. J. Exp. Med. 2011, 208, 2633–2640.
  122. Petillo, S.; Capuano, C.; Molfetta, R.; Fionda, C.; Mekhloufi, A.; Pighi, C.; Antonangeli, F.; Zingoni, A.; Soriani, A.; Petrucci, M.T.; et al. Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: Upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition. Cell Death Dis. 2021, 12, 836.
  123. Domaica, C.I.; Fuertes, M.B.; Rossi, L.E.; Girart, M.V.; Avila, D.E.; Rabinovich, G.A.; Zwirner, N.W. Tumour-experienced T cells promote NK cell activity through trogocytosis of NKG2D and NKp46 ligands. EMBO Rep. 2009, 10, 908–915.
  124. Nakamura, K.; Nakayama, M.; Kawano, M.; Amagai, R.; Ishii, T.; Harigae, H.; Ogasawara, K. Fratricide of natural killer cells dressed with tumor-derived NKG2D ligand. Proc. Natl. Acad. Sci. USA 2013, 110, 9421–9426.
  125. Sheppard, S.; Ferry, A.; Guedes, J.; Guerra, N. The Paradoxical Role of NKG2D in Cancer Immunity. Front. Immunol. 2018, 9, 1808.
  126. Cerwenka, A.; Baron, J.L.; Lanier, L.L. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl. Acad. Sci. USA 2001, 98, 11521–11526.
  127. Diefenbach, A.; Jensen, E.R.; Jamieson, A.M.; Raulet, D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001, 413, 165–171.
  128. Guerra, N.; Tan, Y.X.; Joncker, N.T.; Choy, A.; Gallardo, F.; Xiong, N.; Knoblaugh, S.; Cado, D.; Greenberg, N.M.; Raulet, D.H. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 2008, 28, 571–580.
  129. Smyth, M.J.; Swann, J.; Cretney, E.; Zerafa, N.; Yokoyama, W.M.; Hayakawa, Y. NKG2D function protects the host from tumor initiation. J. Exp. Med. 2005, 202, 583–588.
  130. Babic, M.; Romagnani, C. The Role of Natural Killer Group 2, Member D in Chronic Inflammation and Autoimmunity. Front. Immunol. 2018, 9, 1219.
  131. Oppenheim, D.E.; Roberts, S.J.; Clarke, S.L.; Filler, R.; Lewis, J.M.; Tigelaar, R.E.; Girardi, M.; Hayday, A.C. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat. Immunol. 2005, 6, 928–937.
  132. Coudert, J.D.; Zimmer, J.; Tomasello, E.; Cebecauer, M.; Colonna, M.; Vivier, E.; Held, W. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 2005, 106, 1711–1717.
  133. Coudert, J.D.; Scarpellino, L.; Gros, F.; Vivier, E.; Held, W. Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways. Blood 2008, 111, 3571–3578.
  134. Sheppard, S.; Guedes, J.; Mroz, A.; Zavitsanou, A.M.; Kudo, H.; Rothery, S.M.; Angelopoulos, P.; Goldin, R.; Guerra, N. The immunoreceptor NKG2D promotes tumour growth in a model of hepatocellular carcinoma. Nat. Commun. 2017, 8, 13930.
  135. Rohner, A.; Langenkamp, U.; Siegler, U.; Kalberer, C.P.; Wodnar-Filipowicz, A. Differentiation-promoting drugs up-regulate NKG2D ligand expression and enhance the susceptibility of acute myeloid leukemia cells to natural killer cell-mediated lysis. Leuk. Res. 2007, 31, 1393–1402.
  136. Armeanu, S.; Bitzer, M.; Lauer, U.M.; Venturelli, S.; Pathil, A.; Krusch, M.; Kaiser, S.; Jobst, J.; Smirnow, I.; Wagner, A.; et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 2005, 65, 6321–6329.
  137. Kato, N.; Tanaka, J.; Sugita, J.; Toubai, T.; Miura, Y.; Ibata, M.; Syono, Y.; Ota, S.; Kondo, T.; Asaka, M.; et al. Regulation of the expression of MHC class I-related chain A, B (MICA, MICB) via chromatin remodeling and its impact on the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Leukemia 2007, 21, 2103–2108.
  138. Vales-Gomez, M.; Chisholm, S.E.; Cassady-Cain, R.L.; Roda-Navarro, P.; Reyburn, H.T. Selective induction of expression of a ligand for the NKG2D receptor by proteasome inhibitors. Cancer Res. 2008, 68, 1546–1554.
  139. Zhu, Z.; Lu, X.; Jiang, L.; Sun, X.; Zhou, H.; Jia, Z.; Zhang, X.; Ma, L. STAT3 signaling pathway is involved in decitabine induced biological phenotype regulation of acute myeloid leukemia cells. Am. J. Transl. Res. 2015, 7, 1896–1907.
  140. Okita, R.; Yukawa, T.; Nojima, Y.; Maeda, A.; Saisho, S.; Shimizu, K.; Nakata, M. MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer. Cancer Immunol. Immunother. 2016, 65, 499–509.
  141. Abruzzese, M.P.; Bilotta, M.T.; Fionda, C.; Zingoni, A.; Soriani, A.; Vulpis, E.; Borrelli, C.; Zitti, B.; Petrucci, M.T.; Ricciardi, M.R.; et al. Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: Role of cMYC-IRF4-miR-125b interplay. J. Hematol. Oncol. 2016, 9, 134.
  142. Huang, Y.X.; Chen, X.T.; Guo, K.Y.; Li, Y.H.; Wu, B.Y.; Song, C.Y.; He, Y.J. Sunitinib Induces NK-kappaB-dependent NKG2D Ligand Expression in Nasopharyngeal Carcinoma and Hepatoma Cells. J. Immunother. 2017, 40, 164–174.
  143. McCarthy, M.T.; Lin, D.; Soga, T.; Adam, J.; O’Callaghan, C.A. Inosine pranobex enhances human NK cell cytotoxicity by inducing metabolic activation and NKG2D ligand expression. Eur. J. Immunol. 2020, 50, 130–137.
  144. Veneziani, I.; Infante, P.; Ferretti, E.; Melaiu, O.; Battistelli, C.; Lucarini, V.; Compagnone, M.; Nicoletti, C.; Castellano, A.; Petrini, S.; et al. Nutlin-3a Enhances Natural Killer Cell-Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors. Cancer Immunol. Res. 2021, 9, 170–183.
  145. Poggi, A.; Catellani, S.; Garuti, A.; Pierri, I.; Gobbi, M.; Zocchi, M.R. Effective in vivo induction of NKG2D ligands in acute myeloid leukaemias by all-trans-retinoic acid or sodium valproate. Leukemia 2009, 23, 641–648.
  146. Miyashita, T.; Tajima, H.; Shoji, M.; Nakanuma, S.; Sakai, S.; Makino, I.; Hayashi, H.; Nakagawara, H.; Takamura, H.; Kitagawa, H.; et al. Gemcitabine augments major histocompatibility complex class I-related chain A expression in pancreatic cancer. Gan Kagaku Ryoho Cancer Chemother. 2013, 40, 1600–1602.
  147. Lin, X.; Huang, M.; Xie, F.; Zhou, H.; Yang, J.; Huang, Q. Gemcitabine inhibits immune escape of pancreatic cancer by down regulating the soluble ULBP2 protein. Oncotarget 2016, 7, 70092–70099.
  148. Ferrari de Andrade, L.; Tay, R.E.; Pan, D.; Luoma, A.M.; Ito, Y.; Badrinath, S.; Tsoucas, D.; Franz, B.; May, K.F., Jr.; Harvey, C.J.; et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 2018, 359, 1537–1542.
  149. Kamimura, H.; Yamagiwa, S.; Tsuchiya, A.; Takamura, M.; Matsuda, Y.; Ohkoshi, S.; Inoue, M.; Wakai, T.; Shirai, Y.; Nomoto, M.; et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J. Hepatol. 2012, 56, 381–388.
  150. Sroijak, N.; Ponglikitmongkol, M. 17beta-Estradiol suppresses MHC class I chain-related B gene expression via an intact GC box. Biochem. Cell Biol. 2013, 91, 102–108.
  151. Basu, S.; Pioli, P.A.; Conejo-Garcia, J.; Wira, C.R.; Sentman, C.L. Estradiol regulates MICA expression in human endometrial cells. Clin. Immunol. 2008, 129, 325–332.
  152. Ren, J.; Nie, Y.; Lv, M.; Shen, S.; Tang, R.; Xu, Y.; Hou, Y.; Zhao, S.; Wang, T. Estrogen upregulates MICA/B expression in human non-small cell lung cancer through the regulation of ADAM17. Cell. Mol. Immunol. 2015, 12, 768–776.
  153. Fang, L.; Gong, J.; Wang, Y.; Liu, R.; Li, Z.; Wang, Z.; Zhang, Y.; Zhang, C.; Song, C.; Yang, A.; et al. MICA/B expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2014, 33, 76.
  154. Kim, Y.J.; Li, W.; Zhelev, D.V.; Mellors, J.W.; Dimitrov, D.S.; Baek, D.S. Chimeric antigen receptor-T cells are effective against CEACAM5 expressing non-small cell lung cancer cells resistant to antibody-drug conjugates. Front. Oncol. 2023, 13, 1124039.
  155. Frazao, A.; Colombo, M.; Fourmentraux-Neves, E.; Messaoudene, M.; Rusakiewicz, S.; Zitvogel, L.; Vivier, E.; Vely, F.; Faure, F.; Dreno, B.; et al. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAF(V600E) Melanoma Lines with Vemurafenib. Cancer Immunol. Res. 2017, 5, 582–593.
  156. Zhu, Z.; Bai, Y.; Lu, X.; Ding, J.; Qi, C. Rapamycin downregulates NKG2D ligands in acute myeloid leukemia cells via an activation of the STAT3 pathway: A potential mechanism for rapamycin-induced immune escape in leukemia. Transl. Cancer Res. 2019, 8, 473–482.
  157. Xu, X.; Rao, G.; Li, Y. Xanthine oxidoreductase is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity. Oncotarget 2016, 7, 59220–59235.
  158. Wang, J.; Liu, K.; Xiao, T.; Liu, P.; Prinz, R.A.; Xu, X. Uric acid accumulation in DNA-damaged tumor cells induces NKG2D ligand expression and antitumor immunity by activating TGF-beta-activated kinase 1. Oncoimmunology 2022, 11, 2016159.
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