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Expression profiles for NKG2D ligands in non-neoplastic epithelial tissues. Hierarchical cluster analysis based on the expression profiles of NKG2D ligands demonstrated two distinct ligandbased clusters and three distinct tissue-based clusters: white, N-null type; blue, N-variable type; pink, N-complete type (right side).
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The MHC class I-chain-related proteins (MICs) and the UL16-binding proteins (ULBPs) are inducible stress response molecules that work as activators of a specific receptor, NKG2D, which is expressed on effector cells such as NK cells and subsets of T cells. In order to explore the biological significance of NKG2D ligands in human neoplasms, we compr...
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Background: The major histocompatibility complex class I-related chain A (MICA) molecules play a pivotal role in the modulation of anti-tumor immune responses. A polymorphic change from methionine (Met) to valine (Val) at amino acid position 129 of the alpha 2 heavy-chain categorize MICA alleles into strong and weak binders for the NKG2D receptor....
Citations
... However, their prognostic significance varies considerably between different studies and tumour types. Moreover, NKG2DL expression is heterogeneous not just across different cancer types but also within the same tissues and organs [167]. ...
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. In this review, we consider the underlying biology and regulation of the NKG2D/NKG2DL system and its expression and role in a range of cancer types. We also consider the opportunities for pharmacological modulation of NKG2DL expression while cautioning that such interventions need to be carefully calibrated according to the biology of the specific cancer type.
... Regarding the source of ROS in AA, several endogenous and exogenous factors can cause an accumulation of ROS in HF keratinocytes. As in vitiligo [63], in HF keratinocytes, OS probably induces MHC class I chain-related A (MICA) expression [64]. MICA is a distant homolog of major histocompatibility class I and it is the ligand for the activating receptor NKG2D, expressed in NK cells and CD8+ T cytotoxic cells [65]. ...
Alopecia areata (AA) is a dermatological condition characterized by non-scarring hair loss. Exact etiopathogenesis of AA is still unknown although it is known that several factors contribute to the collapse of the hair-follicle (HF)-immune-privileged (IP) site. Oxidative stress (OS) plays an important role in skin diseases. The aim of this review was to clarify the role of OS in AA pathogenesis and diagnosis, and to discuss potential treatment options. Oxidative-stress markers are altered in serum and skin samples of patients with AA, confirming a general pro-oxidative status in patients with AA. OS induces MHC class I chain-related A (MICA) expression in HF keratinocytes that activates the receptor NKG2D, expressed in NK cells and CD8+ T cytotoxic cells leading to destabilization of the HF immune-privileged site through the production of IFN-γ that stimulates JAK1 and JAK2 pathways. OS also activates the KEAP1-NRF2 pathway, an antioxidant system that contributes to skin homeostasis. In addition, a decrease of ATG5 and LC3B in the hair matrix and an increase in p62 levels indicates a reduction of intrafollicular autophagy during the evolution of AA. Potential biomarkers of OS in AA could be: malondialdehyde (MDA), advanced glycation end-products (AGEs), and ischemic-modified albumin (IMA). JAK inhibitors are the new frontier in treatment of AA and the use of nutraceuticals that modulate the OS balance, in combination with standard treatments, represent promising therapeutic tools.
... These two pathways provide invisibility from NK cells. 24 The average of ULBP5 expression was found higher in endometrial tissue of patients with endometriosis (5.75 + 8.90) and in tumour tissue of patients with endometriosis (2.99 + 5.05) than in control, but was not statistically significant (p = 0.358). The expression of ULBP5 in patients without malignancy is generally low in healthy tissues. ...
Background: Natural killer (NK) cells play a role in pathogenesis of endometriosis. Lower expressions of NK cells receptor group 2D (NKG2D) ligands inhibits cytotoxic activity of NK cells; a common immunity avoidance mechanism in neoplasms. Literatures have proven miRNAs regulatory effect on NKG2D expression. There has been no specific biomarker for diagnosing endometriosis. Non-invasive means of diagnosing endometriosis may reduce well-known risks of invasive method of diagnosis and yield better results. Purpose: To investigate the correlation between miRNA-519a-3p expression with NKG2D ligands (MICA, MICB, ULBP 1-6) on endometriosis and non-endometriosis patients. Methods: This was a cross-sectional study held in five centers: dr. Cipto Mangunkusumo General Hospital, Pelni Hospital, Bunda Hospital, YPK Mandiri Hospital, and Primaya Evasari Hospital from October 2020 to July 2021. miRNA and NKG2DL analysis were done in Human Reproduction, Infertility and Family Planning (HRIFP) cluster at IMERI FKUI. Results: We obtained 19 patients in each study groups. NKG2D ligands and miRNA519a-3p relative expressions were not significantly different (p > 0.05). Increased miRNA519a-3p expression negatively affected NKG2D ligands expression. A decrease in ULBP1 and an increase in ULBP2 increased the probability for endometriosis. NKG2D ligands expression may be influenced by infection, pro-inflammatory cytokine production, dan polymorphism. NKG2D ligands expression level can be different depending on the origin of the sample. Lower expression of miRNA519a-3p indirectly inhibits tumor apoptosis by lowering NKG2D ligands, caspase, or mRNA. Conclussion: We did not manage to establish a correlation between NKG2D ligands with miRNA519a-3p in endometriosis and non-endometriosis patients.
... Indeed, targeting ULBP4, without altering other ligands that might contribute to important immune functions, could yield a very specific therapy. Importantly, it is known that ULBP4 is implicated in various types of cancers [42][43][44] ; however, current data suggest that ULBP4 is not expressed in CNS-related cancers in adults. Although MICA, MICB, and ULBP1-2 are detected at the protein level in human adult glioblastoma multiforme (GBM) and meningioma samples, ULBP3 and ULBP4 are not. ...
Background and Objectives
We posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular stressors inducing the expression of UL16-binding protein 4 (ULBP4), the only detectable NKG2DL. Finally, we evaluate the impact of ULBP4 on functions such as cytokine production and motility by CD8 ⁺ T lymphocytes, a subset largely expressing NKG2D, the cognate receptor.
Methods
Human postmortem brain samples and CSF from patients with MS and controls were used to evaluate NKG2DL expression. In vitro assays using primary cultures of human astrocytes and neurons were performed to identify stressors inducing ULBP4 expression. Human CD8 ⁺ T lymphocytes from MS donors and age/sex-matched healthy controls were isolated to evaluate the functional impact of soluble ULBP4.
Results
We detected mRNA coding for the 8 identified human NKG2DLs in brain samples from patients with MS and controls, but only ULBP4 protein expression was detectable by Western blot. ULBP4 levels were greater in patients with MS, particularly in active and chronic active lesions and normal-appearing white matter, compared with normal-appearing gray matter from MS donors and white and gray matter from controls. Soluble ULBP4 was also detected in CSF of patients with MS and controls, but a smaller shed/soluble form of 25 kDa was significantly elevated in CSF from female patients with MS compared with controls and male patients with MS. Our data indicate that soluble ULBP4 affects various functions of CD8 ⁺ T lymphocytes. First, it enhanced the production of the proinflammatory cytokines GM-CSF and interferon-γ (IFNγ). Second, it increased CD8 ⁺ T lymphocyte motility and favored a kinapse-like behavior when cultured in the presence of human astrocytes. CD8 ⁺ T lymphocytes from patients with MS were especially altered by the presence of soluble ULBP4 compared with healthy controls.
Discussion
Our study provides new evidence for the involvement of NKG2D and its ligand ULBP4 in MS pathology. Our results point to ULBP4 as a viable target to specifically block 1 component of the NKG2D pathway without altering immune surveillance involving other NKG2DL.
... Moreover, as reviewed by Lanier (52), essentially all cell types are capable of expressing one or more types of NKG2D-L if given the appropriate stimulus. For example, Fujita and colleagues (53) identified two distinct ligand expression profiles in non-neoplastic epithelial tissues: ULBP5-ULBP3-MICA/B and ULBP2/6-ULBP1-ULBP4. Moreover, in cells undergoing tumorigenic transformation, high heterogeneity in NKG2D-L expression has been reported. ...
The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.
... Our data also align with those from Wu et al., showing immunoreactivity of MICA/B in neoplastic prostates but not in benign prostate glands (Wu et al., 2004). Fujita et al. however, reported no expression of MICA/B by IHC in both normal prostate tissue and PCa (Fujita et al., 2015). These discordant results may be secondary to different specificity of the utilized reagents. ...
Despite the lack of a complete understanding of the disparities involved, prostate cancer (PCa) has both higher incidence and death rates in African American Men (AAM) relative to those of Caucasian American Men (CAM). MHC class I polypeptide related sequence A (MICA) is an innate immunity protein involved in tumor immunoevasion. Due to a lack of reports of race-specific expression of MICA in PCa, we evaluated MICA expression in patients' tumors and in cell lines from a racially diverse origin. Immunohistochemistry was done on a tissue microarray (TMA) with antibodies against MICA. Tumor MICA mRNA was assessed by data mining using Oncomine and PROGeneV2. Surface MICA and release rate of soluble (s) MICA was evaluated in PCa cell lines originally derived from African American (MDA-PCa-2b) or Caucasian (LNCaP and DU-145) PCa patients. Prostate tumor tissue had a 1.7-fold higher MICA expression relative to normal tissue (p < .0001). MICA immunoreactivity in PCa tissue from AAM was 24% lower (p = .002) compared to CAM. Survival analysis revealed a marginal association of low MICA with poor overall survival (OS) (p = .058). By data mining analysis, a 2.9-fold higher level of MICA mRNA was evidenced in tumor compared to normal tissue (p < .0001). Tumors from AAM had 24% lower levels of MICA mRNA compared to tumors from CAM (p = .038), and poor prognosis was found for patients with lower MICA mRNA (p = .028). By flow cytometry analysis, cell fraction positive for surface MICA was of 3% in MDA-PCa-2b cells, 54% in DU-145 cells, and 67% in LNCaP cells (p < .0001). sMICA was detected in DU-145 and LNCaP cells, but was not detected in MDA-PCa-2b cells. Both LNCaP and DU-145 cells were sensitive to cytolysis mediated by Natural killer (NK) cells. MDA-PCa-2b cells, however were between 1.3-fold at 10:1 Effector:Target (E:T) ratio (p < .0001) and 2-fold at 50:1 E:T ratio (p < .0001) more resistant to NK-mediated cytolysis relative to cells from Caucasian origin.
These results suggest that MICA expression may be related to the aggressive nature of PCa. Our findings also demonstrate for the first time that there are variations in MICA expression in the context of racial differences. This study establishes a rationale for further investigation of MICA as a potential race-specific prognostic marker in PCa.
... In fact, MICA/B has been reported on numerous human cancer types, including lung cancer, and its level of expression can be prognostic. [32][33][34] Thus, a potent means for transformed tumor cells to escape immune detection is to downregulate the surface expression of NKG2D ligands. Despite the ability of NK cells to penetrate the tumor bed, the absence of NKG2D ligands could blind the NK effector cells to the surrounding tumor cells. ...
Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8⁺ T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3ʹuntranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3ʹUTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by antisense TGFβ transfection into H1355 or H1299 tumor cells which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8⁺ T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells.
... Previous reports showed that under normal conditions, nontransformed cells do not express NKG2D ligands [30,31], although dendritic cells and myelomonocytic cells can express NKG2D ligands [22,32]. However, a recent report with more detail methods indicated that there is diverse expression of NKG2D ligands in nonneoplastic tissues with apparently normal histological features, and it was speculated that tumor-associated changes, such as inflammation or immunological reaction, may have occurred in the normal cells and tissues from these patients [33]. From these findings taken together, it is most likely that the NKG2D-NKG2D ligand system plays an important role in tumor immune surveillance. ...
Background and methods:
Natural killer (NK) cells can react with tumor cells through the balance of inhibitory and stimulatory signals between NK cell surface receptors and their ligands, such as MHC class I chain-related A (MICA), MHC class I chain-related B (MICB), and several UL16-binding proteins (ULBPs). In the present study, we evaluated the relationship between NKG2D ligand expression and matrix metalloproteinase (MMP) activity in in vitro culture systems of a panel of gastric cancer cell lines (n = 10) and clinical samples (n = 102).
Results:
First, the surface expression of NK group 2 member D (NKG2D) ligands (MICA, MICB, ULBP-2, and ULBP-3) on tumor cells was markedly downregulated on in vitro culture, in parallel to the upregulation of MMPs analyzed by gelatin zymography and gene expression microarray, whereas the transcript levels of NKG2D ligands remained unchanged on in vitro culture. Second, MMP-specific inhibitors could restore the downregulated expression of NKG2D ligands and functionally improve susceptibilities to NK cells in vitro. Third, the production of soluble NKG2D ligands was increased on in vitro culture and was inhibited by MMP-specific inhibitors. Finally, there was a significant inverse correlation between MMP-9 expression and NKG2D ligand expression as analyzed by immunohistochemistry in clinical tumor samples.
Conclusion:
The present study is a comprehensive study demonstrating that upregulation of MMP activity can induce a downregulation of expression of NKG2D ligands in gastric cancer cells, leading to lower-level susceptibility to NK cells.
Targeted therapies and immune checkpoint inhibitors have advanced the treatment landscape of Renal Cell Carcinoma (RCC) over the last decade. While checkpoint inhibitors have demonstrated survival benefit and are currently approved in the front-line and second-line settings, primary and secondary resistance is common. A comprehensive understanding of the mechanisms of immune evasion in RCC is therefore critical to the development of effective combination treatment strategies. This article reviews the current understanding of the different, yet coordinated, mechanisms adopted by RCC cells to evade immune killing; summarizes various aspects of clinical translation thus far, including the currently registered RCC clinical trials exploring agents in combination with checkpoint inhibitors; and provides perspectives on the current landscape and future directions for the field.
