|Year : 2016 | Volume
| Issue : 4 | Page : 1224-1233
Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies
Department of Biomedical Sciences, School of Bio Sciences and Technology,VIT University, Vellore, Tamil Nadu, India
|Date of Web Publication||7-Feb-2017|
P K Suresh
School of Bio Sciences and Technology, VIT University, Vellore - 632 014, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Major histocompatibility complex Class I-related chain A/chain B (MICA/MICB) is stress-inducible, highly polymorphic ligands whose expression at the transcript level has been detected in all tissues except the central nervous system. However, their restricted protein expression is due to their regulation at the posttranslational level. Its levels are elevated in virally infected and neoplastically transformed cells. Membrane expression of this NKG2DL marks the aberrant cells for elimination by those immune effector cells that express the cognate NKG2D receptor. Among the evasion strategies developed by tumors, the metalloprotease-dependent shedding of MICA/MICB from tumors (either the free or the exosome form) can contribute to the inhibition of cytolysis by the immune effector cells (all NK cells, most NKT cells; γδ CD8+ T cells and αβ CD8+ T cells, as well as some αβ CD4+ T cells). There are micro-RNA clusters that regulate surface expression and shedding. Polymorphic variants can be used as susceptibility/associative markers and can also possibly be used to correlate with tumor survival as well as staging/grading of tumors. Variations in the expression level require quantification of this marker for diagnostic/prognostic and therapeutic purposes. Mechanism-based studies would provide a better tumor-specific understanding of their relative roles in the processes of tumor cell elimination versus growth and progression. Last but not least, conventional, interlaboratory validated assays (for, e.g., antibody-based methods) should be replaced by robust, reproducible, feasible biophysics-based methods using tumor biopsies. Further, correlative DNA polymorphism-based studies can be done using biological fluids (for, e.g., human saliva) that can be sampled by minimally invasive means.
Keywords: Major histocompatibility complex Class I-related chain A/chain B, neoplastic transformation, NKG2D, polymorphism, soluble major histocompatibility complex Class I-related chain A/chain B, stress-inducible ligand, virally infected
|How to cite this article:|
Suresh P K. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies. J Can Res Ther 2016;12:1224-33
|How to cite this URL:|
Suresh P K. Membrane-bound versus soluble major histocompatibility complex Class I-related chain A and major histocompatibility complex Class I-related chain B differential expression: Mechanisms of tumor eradication versus evasion and current drug development strategies. J Can Res Ther [serial online] 2016 [cited 2017 Feb 24];12:1224-33. Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1224/176169
| > Introduction|| |
The major histocompatibility complex Class I-related chain A/chain B (MICA/MICB) is a highly divergent, polymorphic human leukocyte antigen (HLA) Class I-related gene and is known to act as molecules/ligands signaling cellular distress. They form part of the eight surface glycoproteins along with the UL16-binding proteins (ULBPs) family of six proteins. Unlike classical HLA molecules, they are not involved in antigen presentation. As on date, 70 MICA and 30 MICB alleles have been discovered, apart from a few variants reported for those in the ULBP family. MICA/MICB carry three domains (α1, α2, and α3) that resemble the major histocompatibility complex (MHC) Class I family (murine equivalent of the HLA). The two MHC Class I-like domains (α1 and α2) are found among members of the ULBP family. Retinoic acid early inducible-1 protein is the ortholog for the ULBP proteins in mice (expression driven by the Ras pathway ), while there are no known orthologs of MICA/MICB in the same model system. However, mice express the ligands murine ULBP-like transcript 1 and the minor histocompatibility antigen H60., These MHC ligands have a role in cytotoxicity, proliferation and cytokine secretion. The MICA gene has an unusual intron-exon structure and a variable expression pattern (expressed especially in fibroblasts and epithelial cells). It may have the ability of binding short peptides or ligands , and is widely believed not to be involved in antigen presentation. While the variable/restricted expression pattern may be attributed by some to be due to its decreasing functional importance, there is sufficient evidence in the literature of its mechanistic role in immune activation. This activation should be seen in the context of tumor surveillance, apart from its role in eliminating virally infected cells. This inducible ligand, expressed on target cells, interacts with the NKG2D receptor on immune cells prior to their destruction. This information has been documented based on studies in several in vivo and in vitro model systems. The importance of this interaction can be gauged by the fact that NKG2D deficient mice have an increased rate of tumor formation.In vitro and model system-based studies indicate that EMT processes have been associated with the invasive and metastatic tumor phenotype. This process has been shown to mediate antitumor responses via the NKG2D/NKG2DL system. Uncontrolled proliferation in tumor cells may be due to NKG2D expression and signal transduction via the phosphoinositide-3-kinase (PI3-K) and MAPK pathway. Evolving tumors can also shed/down-regulate MHC Class I antigen on their surface and be involved in immunosuppression. Apart from the mechanistic role of membrane-bound MICA/soluble MICA (sMICA), association of the gene encoding for the protein as well as its variants have been associated with several precancerous and cancerous conditions. This association would serve to flag individuals that may be susceptible to cancer. In this regard, certain combinations of HLA-B and MICA/MICB haplotypes (closely linked to the HLA-B molecule) have been shown to exhibit linkage disequilibrium as per the Hardy-Weinberg law. Further, polymorphic variants may result in the production of the aforesaid sMICA/sMICB. Apart from their mechanistic relevance, quantification of their levels may be of benefit for evaluating the immune status of the individual. This review highlights the anatomic localization, signal transduction mechanisms as well as the importance of this immune surveillance mechanism in tumor eradication as well as the evasion strategies developed by cancerous cells. Last but not least, an improved understanding of the mechanisms has paved the way for the development of drugs that can selectively reverse deleterious epigenetic changes in cancers.
Variations in anatomic and cellular localization of major histocompatibility complex Class I-related chain A/chain B has the final word been said?
In humans, their expression at the protein level may be restricted under normal physiological conditions. Reports in the literature have demonstrated its expression mainly in the thymus and the gastrointestinal epithelium. In the case of the gastrointestinal epithelium, this extensively glycosylated transmembrane protein does not form a heterodimer with the β2–macroglobulin. This protein is conformationally stable in the absence of bound peptide ligands (unlike the classical HLA-Class I molecules) and is believed to be activated by a heat shock protein. Further, its expression is also involved in activating a group of T cells in the intestinal intraepithelial lymphocyte compartment. Its expression in the external epithelial layer of Hassal's corpuscles within the thymic medullary region has been shown to be associated with the maturation of single positive thymocytes (SP CD8+ cells). A recent whole body tissue scan study has documented the in vivo RNA expression of MICA and MICB in all tissues except the central nervous system. This finding challenges the hitherto accepted universal view that expression is limited under physiological/homeostatic conditions. This finding may mean that the protein is widely translated and is membrane-bound in all human tissues. However, an inhibition of translation and/or increased degradation of the protein cannot be discounted by these findings, apart from posttranslational regulation. Apart from their reported expression in physiological/”stressful conditions,” its expression has been widely reported in virally infected as well as neoplastic cells. Its recognition by the γδ T cells was broad in terms of its recognition of MICA/MICB in many carcinomas including but not restricted to those of the lung and the oral cavity. This induction may be modulated by the tumor microenvironment influencing the homeostatic conditions favoring tumor growth. NKG2D ligands are usually expressed in tumor epithelia in several sites. The sites include the breast, ovary, lung, colon, kidney, pancreas, gliomas, and melanomas. Despite frequent co-expression, in some tumor cell lines surface expression is restricted to only one of the aforesaid NKG2D ligands. Further evidence has been obtained from leukemic cell lines about NKG2D ligand expression. However, there is conflicting data with respect to the physiological NKG2DL expression. Evidence from cell culture experiments has however shown that this gene is expressed in fibroblasts and endothelial cells on the surface. However, surface expression was not observed in the case of keratinocytes, monocytes  as well as B- and T-cells. Taken together, variation in the expression levels (anatomic and cellular localization) in different physiological and pathophysiological contexts warrants a systematic re-analysis of its abundance and functional importance/role in tumor surveillance and evasion mechanisms. In this regard, the availability of conditional knocks-out mice wherein deficiencies of specific regulators of this stress ligand (for, e.g., interleukin-10 [IL-10]) can be correlated with expression (surface or the shed form) and functional capabilities. More importantly, well-designed human case–control studies (with an adequate sample size) for the quantification of these ligands using corroborative methods will enable us to determine the reference levels of these ligands in physiological conditions versus in patients with specific tumors. This approach can aid in possibly improving their predictive power of the existing battery of markers in terms of prognosis.
| > NKG2D/NKG2DL Signal Transduction Mechanisms and Regulation|| |
This interaction was shown to involve MICA-mediated delivery of signal 1 and signal 2. The first signal is T-cell receptor-dependent, while the second co-stimulatory signal is NKG2D-dependent. Its specificity was evident since the V (δ1) γδ T cells could not recognize those cells expressing the highly divergent ULBP/N2DL ligands of NKG2D. Apart from the γδ T-cells, NKG2D receptors in the NK-cells also interact with MICA through their adaptor molecules DAP10 and DAP12, with co-stimulatory and stimulatory functions, respectively. DAP10 is positively regulated by IL-2 and is negatively regulated by transforming growth factor-β. The p85 subunit of PI3-K as well as Grb2-Vav1 is phosphorylated by the adaptor protein. This modification improves the survival and cytotoxicity of NK-cells apart from co-stimulatory signals being provided to the T-cells. However, extended stimulation affects the functional capabilities of both T- and NK-cells. This is NKG2D-mediated and is due to the Fas/Fas ligand-dependent caspase-3/-7 activation and subsequently leads to CD3ζ chain degradation. IL-17 production, via NKG2D signaling, is increased in human T cells in chronic inflammations and during an infection. In CD8+ T cells (no DAP12), the interaction with DAP10 results in a co-stimulatory signal only. Regulation of the various types of NKG2DL is context-dependent. Information about mechanistic aspects of MICA regulation was obtained from cell-based systems following LPS-mediated stimulation of human macrophages through the ligand interacting with its cognate receptor (TLR4). The regulation was at the transcriptional level in terms of increased stability. Further, posttranscriptional regulation was done by ATM and ATR RAD3-related kinases. Last but not least, downregulation of specific miRNA (miR-17-5; miR-20a; miR-93) can contribute to the increased expression of MICA at the surface. This subsection provides a rationale for, and the mechanisms involved in signal transduction processes for MICA/MICB-mediated cytolysis of aberrant tumor cells. This information would be of significance to the tumor biologist as well as clinical researchers.
| > Significance of Membrane-Bound Major Histocompatibility Complex Class I-Related Chain A/chain B in Tumor Eradication|| |
The engagement of the NKG2D receptor on the aforesaid cytotoxic effector cells with MICA/MICB expressed on the surface of cancer cells is the initial event in the eradication of tumor cells. This cytotoxicity was dependent on and correlatable with the surface expression of molecules like MICA. Several lines of corroborative evidence, from cell-based and in vivo experimental systems, point to this commonality in the mechanism(s) of NK cell-mediated cytolysis of tumorigenic cells and is summarized in the form of a table [Table 1] and is based on ex vivo or in vitro data from human samples.
|Table 1: Corroborative evidence for the role of surface MICA/MICB in tumor eradication (original)|
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Despite this common theme, their relative involvement (MICA vs. MICB) as well as their possible cooperative role is antitumor-specific. Further, in certain types of cancers, these ligands are sorted and shed into the exosomal compartment (please see below). These molecules singly and/or in combination with those found in exosomes contribute to a diminished NK-cell-mediated antitumor response. However, in certain cases, dendritic cell-derived ligands have been shown to augment NK-cell-mediated cytotoxicity. Taken together, the use of appropriate model systems is necessary to mimic or model the unique/overlapping expression patterns in the tumor microenvironment and to evaluate the relative role of each of the contributing mechanisms. This is also important as the evolving tumor develops tumor-specific homeostatic/adaptive mechanisms conducive for its growth. Last but not least, apart from these ligands, there are 6 UL16 binding proteins which have been shown to have complementary/overlapping functions. However, the need of the hour is to quantify the surface expression of MICA/MICB, in humans and correlate the same with the different stages of tumor progression (based on accepted clinicopathological and molecular correlates).
| > Soluble Mica: Mechanism of Downregulation And/or Release|| |
Hypoxia with the concomitant increase in HIF-1α can down-regulate the expression of MICA/MICB in osteosarcoma cells without an increase in the sMICA levels. This may be due to an inhibition of translation or an increased degradation of the protein and is independent of the hypoxia-linked decrease in the production of NO metabolites (nitrite and nitrate). Shedding of NKG2DL  like MICA and/or release into exosomes by tumor cells can contribute to antitumor responses. This mechanism is considered as one of the important escape strategies adopted by these cells. sMICA down-regulates NKG2D on NK-cells and hence an immune response is impaired. This downregulation was also observed on NK-cells cultured with the sera of a leukemia patient. Further, in certain tumors, sMICA levels have been correlated with tumor progression. Proteolytic cleavage of MICA has shown to require the recruitment of, as well as the functional association with disulfide isomerase endoplasmic reticulum. This shedding has been shown to be promoted by the palmitoylation of key cysteine residues in MICA/MICB, which may hinder the ubiquitylation of adjacent important lysine residues. Thus, the ligand is protected from degradation, and the palmitoylation is also an important determinant for it being sorted to the cholesterol/caveolin-1-enriched microdomain. This sorting is necessary for the proteolytic cleavage mediated by metalloproteinases - disintegrin and metalloproteinase domain-containing protein 10 and 17 (ADAM10 and ADAM17). MICA and MICB overexpressing transfectants have shown that MICB is selective for ADAM17 while MICA is a substrate for both enzymes. ADAM9 is also involved in shedding MICA in hepatocellular cell lines. Specifically, siRNA-based knockdown of the protein increased membrane expression of MICA and decreased the levels of soluble MICA. Similar results were obtained following treatment with sorafenib - a chemical inhibitor of ADAM9. Mechanistic studies alluded to the possibility of the existence of an additional (ADAM9-independent) cleavage site on the MICA protein. Variability in the cell line-specific substrate specificities of the different enzymes was also demonstrated. In the case of Panc89 cells, both enzymes are needed for soluble MICA production while sMICB requires ADAM17 largely. In the case of Panc-Tu1, sMICA requires ADAM17 while soluble MICB requires ADAM10 and ADAM17. Last but not least, in the case of PC3 cells, MICA was sorted to the exosomal compartment due to a polymorphic variant (MICA*008 - A5.1 microsatellite polymorphism) which is seen in about 21–47% of populations globally (please refer to the section below on polymorphisms) resulting in a truncation intracellularly. This variant has been shown to be shed into these small membrane vesicles (secreted after fusion with the plasma membrane). Further, differences in its transmembrane and cytosolic domains have also been reported. Incubation of MICA*008 containing exosomes resulted in the downregulation of NKG2D and the results obtained were independent of the surface expression of the ligand on the target cells. In the case of sMICB, ADAM17 was shown to be largely involved. In breast cancer cells, MDA-MB231, ADAM17 is the major proteolytic agent for both forms (MICA and MICB). In the case of MICB, its half-life in the plasma membrane is short. This short half-life has been attributed to it being recycled in the inner compartments (Golgi/endosomal) and due to its shedding to the extracellular medium. Internalization is due to the lipid environment and also involves a clathrin-dependent mechanism.
The mechanism of shedding and release extracellularly (free or the exosome form) can improve our understanding of the aberrations of MICA/MICB-based immune surveillance in human cancers. Further, quantification of sMICA levels using cost-effective methods would pave the way for the development of reference values subsequent to their correlation with widely accepted clinicopathological correlates and DNA polymorphism-based molecular markers. Inherent in this strategy is the unmet need for interlaboratory validation of functional assays and global multicentric studies. In this regard, the feasibility of collecting human saliva samples (relatively noninvasively) provides opportunities for developing and/or validating polymorphism-based signatures. Last but not least, this approach can possibly also improve the predictive power of the existing battery of markers.
| > Role and Significance of Soluble Major Histocompatibility Complex Class I-Related Chain A/chain B and Tumors|| |
sMICA has been shown to be elevated in the sera of patients with different malignant conditions. However, their levels were found to be elevated in benign conditions as well. Hence, while its role as a screening tool may be limited, its role in differential diagnosis is important as it has been shown to be good in discriminating between lung cancer patients and controls. This aspect when validated and compared with other lung tumor markers can help in diagnosis. The information in [Table 2] provides corroborative evidence (for sMICA and sMICB) based on in vitro/ex vivo data.
|Table 2: Corroborative Evidence for the role and significance of sMICA/sMICB and tumors|
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Corroborative data provide an impetus to further screen (for, e.g., using RNAi/chemicals-based functional screens in multiple model systems) for further delineating the regulators of MICA/MICB expression. This approach can potentially aid in the identification of novel regulators of expression of these ligands induced during stressful conditions/to combat virally infected cells and cancer cells.
| > Virally-Mediated Tumorigenic Cells-Molecular Mechanisms of Major Histocompatibility Complex Class I-Related Chain A/chain B Downregulation|| |
The evolution of immune evasion mechanisms in the human cytomegalovirus (HCMV) is associated with the downregulation of MICA and MICB via the induction of viral glycoproteins UL142 and UL16, respectively. The UL16-mediated downregulation/sequestration of MICB affects its maturation and transit involving the trans-Golgi network. UL142 sequesters MICA in the cis-Golgi apparatus. However, other alleles of the NKG2DL are not affected, and this is an example of the host having back-up mechanisms to combat viral infections., Individuals harboring the MICA*008 allele are resistant to HCMV-mediated cancers. However, this virus produces US9 glycoprotein that can specifically target this variant and combat host immunity. Apart from targeting the MICA allele variants (MIC*008) exposed on the surface of tumors, increased virally-mediated shedding of MICA (increase in sMICA in serum) has been attributed to be due to an increase in ADAM17 and MP14. Further, cellular as well as CMV-encoded miRNA down-regulate TIMP3. Hence, this is another strategy adopted by viruses to evade host immunity. A micro-RNA (miR293) was reported to be down-regulated in hepatitis-B infected primary hepatocytes (a cell-based model system for HBV-mediated cellular carcinoma). This miRNA was known to regulate MICA protein levels. Hence, administration of the same miRNA could possibly restore the balance between the expression levels of MICA (membrane and soluble levels). Conversely, over-expression of 25-93-106b cluster can suppress MICA expression in HCC cells. Hence, silencing this miRNA cluster would restore expression. This hypothesis was tested and validated in an in vitro and an in vivo cell killing assay. It is widely recognized that one of the risk factors for HCC is Hepatitis B surface antigen seropositivity. An antigen was associated with the upregulation of specific miRNA. This miRNA, in turn, bound to the 3' UTR of MICA/MICB and contributed to its/their downregulation. Hence, such cells were relatively less sensitive to NK cell-mediated cytolysis. The association of specific MICA and MICB polymorphisms in colorectal cancer was observed. The A4 and the A5 alleles, respectively, (variants in the TM region) were directly and inversely correlated with advanced stages of the disease process. For those with the latter allele, there was an improvement in patient survival with the tumors exhibited microsatellite stability. Among colorectal cancer patients, those harboring the A4 allele (MICA-TM) had a relatively lower chance of survival in comparison with controls. This section further underscores the importance of the NKG2D/NKG2DL system and the mechanisms evolved by viruses to subvert the immune surveillance strategies. Corroborative evidence is also provided by the identification and analysis of polymorphic variants altering the susceptibility of tumor cells to cytolysis due to alterations in the expression of MICA/MICB.
| > Major Histocompatibility Complex Class I-Related Chain A/chain B Expression and Possible Drug Development Strategies|| |
The aforesaid review provides evidence of the mechanisms involved in regulating the NKG2D/NKG2DL (MICA/MICB) system and cytolysis of virally infected and cancer cells. Knowledge of the mechanisms and validation of the druggable targets has paved the way for the development and/or refinement of the existing drugs that include those that are developed against epigenetic modifiers. [Table 3] provides evidence for the drug development strategies in relation to the membrane expression of MICA/MICB.
| > Conclusions|| |
The overlapping/unique tumor-specific variations in the expression level of MICA/MICB warrant a more systematic analysis of the molecular aspects regulating their localization/expression (membrane-bound; exosome or secreted form). Since there are redundancy/back-up mechanisms, other ligands that can complement their functions should also be analyzed. Further, the need of the hour is for interlaboratory validation of assays to obtain more accurate reference/basal values of this inducible stress ligand (both the membrane-bound and exosome or secreted forms) as well as quantify their levels in virally infected and cancer-afflicted individuals from biopsied tumor specimens. Further, correlative DNA polymorphism-based studies can be done using biological fluids (for, e.g., human saliva) that can be sampled by minimally invasive means. Last but not least, the prohibitive cost of assays (for, e.g., antibody-based methods) necessitates the application/validation of assays that exploit the biophysical properties of these molecules.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]