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Natural killer cells (NK) are the "professional killer" of tumors and play a crucial role in anti-tumor immunotherapy. NK cell desensitization is a key mechanism of tumor immune escape. Dysregulated NKG2D-NKG2DL signaling is a primary driver of this desensitization process. However, the factors that regulate NK cell desensitization remain largely uncharacterized. Here, we present the first report that circular RNA circARAP2 (hsa_circ_0069396) is involved in the soluble MICA (sMICA)-induced NKG2D endocytosis in the NK cell desensitization model. CircARAP2 was upregulated during NK cell desensitization and the loss of circARAP2 alleviated NKG2D endocytosis and NK cell desensitization. Using Chromatin isolation by RNA purification (ChIRP) and RNA pull-down approaches, we identified that RAB5A, a molecular marker of early endosomes, was its downstream target. Notably, transcription factor CTCF was an intermediate functional partner of circARAP2. Mechanistically, we discovered that circARAP2 interacted with CTCF and inhibited the recruitment of CTCF-Polycomb Repressive Complex 2 (PRC2) to the promoter region of RAB5A, thereby erasing histone H3K27 and H3K9 methylation suppression to enhance RAB5A transcription. These data demonstrate that inhibition of circARAP2 effectively alleviates sMICA-induced NKG2D endocytosis and NK cell desensitization, providing a novel target for therapeutic intervention in tumor immune evasion. [ABSTRACT FROM AUTHOR]

Objective: Variations in immune responses to viral particles and antiretroviral drugs show interference of the cluster of differentiation number 4 T cell monitoring methods, leading to an inaccurate evaluation for human immunodeficiency virus infected patients receiving antiretroviral therapy. Other biological markers; such as cytokine; especially interferon gamma (IFN-γ) and soluble molecules of major histocompatibility complex class I chain related molecule A (sMICA), were designed as a novel severity marker. Material and Methods: Levels of IFN-γ and sMICA were evaluated for 69 patients, who presented with HIV infection; with no other diseases or inflammation. The candidates were classified into four groups, depending on their CD4 T cell count. The IFN-γ and sMICA serum content of the patients was detected in triplicate, using enzyme-linked immunosorbent assay. Results: Mean value of IFN-γ in each severity group was 49.1±9.7, 69.1±21.8, 63.0±12.8, and 69.4±18.4 picograms/ milliliter for none, mild, advanced, and severe cases, respectively. sMICA was detected at 36.8±19.6, 134.7±122.5, 33.6±12.4, and 83.9±40.0 international unit/milliliter, respectively. A significant association between IFN-γ and CD4 cells of normal anti-retroviral treatment response, defined by CD4 cells and viral loads, was observed using Spearman correlation, with p-values 0.033, r -0.434, 0.026 and -0.321, respectively. Conclusion: IFN-γ and sMICA were found to be associated with the CD4 count in the normal responses to antiretroviral treatment. This suggested that IFN-γ could be used as a biological marker for monitoring of immunological severity during anti-retroviral responses.

Background: AML is a leukemic disease that related to the rapidly myeloid proliferation progenitor cells are transformed and leading to stop proliferation and self-renewing. AML have many abilities to evading immune system one of them down expression of NK cells activating receptors NKG2D which is elaborate in in cooperation innate and adaptive immunities, and occupations as a "principal switch" in influential the stimulation of natural killer (NK) cells. NKG2D can binds to a various ligand molecule, which are only expressed at small concentration in usual cells but can be increase by a cellular tension response. And the realizing soluble NKG2D ligands MICA which is express by tumor cells and by binding with NKG2D lead to activated NK cells. Patients and methods: This study consists of 30 new diagnosed patients with AML and 24 out of 30 patients follow up at 14 days after treatment, 20 healthy looking persons match age and sex as control group. NKG2D detection by Flowcytometry and soluble MICA detection by ELISA. Results: The NK cells activation receptor down expression in patients of AML as well as increase releasing of soluble ligand MICA. Conclusion: The NKG2D in patients with AML down expression which may due to increase soluble ligand MICA which lead to mask NKG2D receptors. There was relationship between down expression of NKG2D besides releasing soluble ligand MICA. [ABSTRACT FROM AUTHOR]

BackgroundThe aim of this study was to analyze the clinical efficacy of different thoracoscopic procedures in patients with non-small cell lung cancer and their correlation with matrix metalloproteinase-7 mRNA (MMPs-7 mRNA) and soluble major histocompatibility complex class I molecule A (sMICA), as well as their effect on T-cell subsets.MethodsA total of 100 patients with non-small cell lung cancer who received different thoracoscopic surgeries were divided into the Control group (three-port thoracoscopic surgery) and the study group (single-port thoracoscopic surgery). The two groups were evaluated to compare the perioperative indicators, MMPs-7 mRNA, sMICA expression levels, T-cell subsets, postoperative pain, complication rates, and prognostic outcomes at 1-year follow-up.ResultsThe operation time, blood loss, drainage tube placement time, incision length, and hospital stay in the study group were less than those in the control group (P < 0.05). There was no significant difference in the number of lymph node dissections between the two groups (P > 0.05). After 3 days, the expression levels of MMPs-7 mRNA and sMICA in the study group were lower than those in the control group (P < 0.05); CD4 +, CD8 +, and CD4 +/CD8 + in the study group were higher than those in the control group (P < 0.05). On days 1, 3, and 5, the visual analog score (VAS) of the study group was lower than that of the control group (P < 0.05); there was no significant difference in the complication rate between the two follow-up groups (P > 0.05), in which all patients completed the follow-up. After 1 year of follow-up, there was no significant difference in the tumor-free survival rate and overall survival rate between the two groups (P > 0.05).ConclusionCompared with three-port thoracoscopic surgery, single-port thoracoscopic surgery can improve perioperative expression, shorten hospital stay, reduce serum tumor micrometastasis levels, improve immune metastasis mechanisms and reduce pain, which is of great significance to patients with non-small cell lung cancer. It is an effective, convenient, and safe surgical option that deserves wide clinical reference.

Background/aims: The genome-wide association study has shown that MHC class I chain-related A (MICA) genetic variants were associated with hepatitis C virus (HCC) related hepatocellular carcinoma. The impact of the genetic variants and its serum levels on post-treatment cohort is elusive. Methods: MICA rs2596542 genotype and serum MICA (sMICA) levels were evaluated in 705 patients receiving antiviral therapy. Results: Fifty-eight (8·2%) patients developed HCC, with a median follow-up period of 48·2 months (range: 6–129 months). The MICA A allele was associated with a significantly increased risk of HCC development in cirrhotic non-SVR patients but not in patients of non-cirrhotic and/or with SVR. For cirrhotic non-SVR patients, high sMICA levels (HR/CI: 5·93/1·86–26.38·61, P = 0·002) and the MICA rs2596542 A allele (HR/CI: 4·37/1·52–12·07, P = 0·002) were independently associated with HCC development. The risk A allele or GG genotype with sMICA > 175 ng/mL provided the best accuracy (79%) and a negative predictive value of 100% in predicting HCC. Conclusions: Cirrhotic patients who carry MICA risk alleles and those without risk alleles but with high sMICA levels possessed the highest risk of HCC development once they failed antiviral therapy.

MICA is a stress-induced protein that, as a rule, is not expressed in healthy tissues, but appears in large amounts on the surface of cells undergoing malignant transformation. In humans, this protein can either initiate antitumor immune response, or facilitate tumor cells for their escape of destruction. After shedding from tumor cell surface, soluble MICA enters blood circulation and contributes to decreased activity of effector cells, due to inactivation of NKG2D receptor. The aim of our study was to determine differences in circulating sMICA concentrations in sera of patients with different types of malignant lymphomas, and to evaluate the impact of sMICA upon NKG2D-positive cytotoxic lymphocytes. In experimental models with C1R-MICA cells, the MICA shedding was shown to occur from the surface of cultured tumor cells into the extracellular space. A reduced NKG2D expression dependent on sMICA concentration in the culture medium was demonstrated by flow cytometry in peripheral mononuclear cells, thus suggesting a role of serum sMICA in suppression of antitumor immune response. The sMICA detection was performed in patients with various types of B- or T-cell non-Hodgkin’s lymphomas by means of enzyme-linked immunosorbent assay. The groups of patients with increased sMICA content were identified and compared with the control group. Minimal amounts of serum sMICA were registered in the control group, with the median of 20 pg/ml. In a combined group of patients with various B-cell lymphomas, an increase in circulating sMICA amounts was shown, at the levels of more than 6.5 times exceeding the control values. The highest values of sMICA were recorded among the patients with chronic lymphocytic leukemia, diffuse large cell lymphoma, and multiple myeloma. Maximal sMICA levels among the investigated groups of patients were observed in the group of patients with T-cell anaplastic lymphoma (median of 574 pg/ml). The study provides preliminary evidence for a suppressive effect of different (immuno)chemotherapy components, in particular, rituximab and radiation therapy, upon serum sMICA contents in the lymphoma patients. Thus, elevated serum sMICA levels in patients with hematological malignancies may be considered as an additional criterion for application of the antitumor therapy. sMICA monitoring at different stages of cytostatic treatment may be useful in order to evaluate its efficiency.

Jiong Chen,1,2,* Hong Xu,1,2,* Xing-Xing Zhu1,21Department of General Surgery, Affiliated Provincial Hospital, Anhui Medical University, 2Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, People’s Republic of China*These authors contributed equally to this workAbstract: Soluble major histocompatibility complex class I-related chain A molecules (sMICA) and natural-killer group 2 member D (NKG2D) not only correlate with tumorigenesis and progression, but also with tumor invasion and metastasis. In this study, we used immunohistochemistry to investigate the correlation and prognostic significance of the differential expression of sMICA and NKG2D in pancreatic carcinoma and paracarcinoma tissues from 70 patients with pancreatic carcinomas. The results showed that sMICA expression was significantly (P

The polymorphic major histocompatibility complex class I chain-related molecule A (MICA) and its soluble form (sMICA) interact with activating receptor natural-killer group 2 member D (NKG2D) on natural-killer (NK) and T cells, thereby modifying immune responses to transplantation and infectious agents (e.g., cytomegalovirus). Two single-nucleotide polymorphisms (SNPs), rs2596538GA in the MICA promoter and rs1051792AG in the coding region (MICA-129Val/Met), influence MICA expression or binding to NKG2D, with MICA-129Met molecules showing higher receptor affinity. To investigate the impact of these SNPs on the occurrence of cytomegalovirus infection or acute rejection (AR) in individuals who underwent simultaneous pancreas–kidney transplantation (SPKT), 50 recipient-donor pairs were genotyped, and sMICA levels were measured during the first year post-transplantation. Recipients with a Val-mismatch (recipient Met/Met and donor Val/Met or Val/Val) showed shorter cytomegalovirus infection-free and shorter kidney AR-free survival. Additionally, Val mismatch was an independent predictor of cytomegalovirus infection and kidney AR in the first year post-transplantation. Interestingly, sMICA levels were lower in rs2596538AA and MICA129Met/Met-homozygous recipients. These results provide further evidence that genetic variants of MICA influence sMICA levels, and that Val mismatch at position 129 increases cytomegalovirus infection and kidney AR risk during the first year post-SPKT. [ABSTRACT FROM AUTHOR]

Background/aims: Genetic variants of MHC class I polypeptide-related chain A (MICA) at rs2596542 have been associated with hepatocellular carcinoma. The linkage between serum MICA (sMICA) and liver fibrosis in chronic hepatitis C is elusive., Results: Linear regression analysis revealed that sMICA were independently correlated to α-fetoprotein (β: 0.149; 95% confidence interval [CI]: 0.001, 0.003; P = 0.007)and MICA rs2596542 GG genotype (β: 0.209; 95% CI: 0.153, 0.483; P < 0.001). While patients were stratified by MICA genetic variants, advanced fibrosis was the only factor independently correlated to sMICA among A allele carriers (β: 0.234; 95% CI: 0.107, 0.543; P = 0.004) but not among non-A allele carriers. Logistic regression analysis revealed that factors associated with advanced liver fibrosis was sMICA (OR/CI: 2.996/1.428-6.287, P = 0.004) and platelet counts (OR/CI: 0.988/0.982-0.994, P < 0.001) in MICA rs2596542 A allele carriers. sMICA > 50 pg/mL provided a positive predictive value of 72 % in predicting advanced liver fibrosis (F3-4) and of 90% in significant fibrosis (> F2) in MICA rs2596542 A allele carriers., Materials and Methods: Serum level and single nucleotide polymorphism at rs2596542 of MICA were tested for the association with liver fibrosis in 319 biopsy proven chronic hepatitis C patients., Conclusions: Levels of sMICA were highly correlated to liver disease severity in chronic hepatitis C patients who carried the MICA rs738409 A allele. Patients possessing the genetic predisposition had a higher likelihood of progressed liver fibrosis if they expressed higher sMICA levels.

Dysfunction of natural killer (NK) cells has been implicated in the failure of antitumor immune responses in hepatocellular carcinoma (HCC) patients. However, the changes of NK profile in peripheral blood after surgery and tumor tissues of HCC patients, as well as the underlying reason and the significance are vague. Here, we observed that the frequencies of circulating NKG2D+CD56dimNK cells decreased significantly in HBV-related HCC and were negatively correlated with the levels of serum TGF-β and soluble MICA (sMICA).In vitroexperiments confirmed that the TGF-β and sMICA in tumor tissue homogenates, as well as sMICA in HCC cells culture supernatants could reduce the frequency of NKG2D+CD56dimNK cells. In addition, in HCC patients the lower frequency of circulating NKG2D+CD56dimNK cells was associated with larger tumor size and/or higher serum GGT. Noticeably, the frequency of NKG2D+CD56dimNK cells at one month after surgery usually failed to restore in early recurrent patients, and that frequency was negatively associated with early recurrence and shorter overall survival. These results suggest that declined frequency of NKG2D+CD56dimNK cells in HCC was associated with higher TGF-β and sMICA production, and low frequency of circulating NKG2D+CD56dimNK cells at one month after surgery may predict poor prognosis of HBV-related HCC patients accepting hepatectomy. [ABSTRACT FROM PUBLISHER]

Background and Objective: Human major histocompatibility complex class I-related gene A (MICA) is reportedly associated with poor transplant outcomes and a high risk of acute and chronic rejection in solid organ transplantation. However, studies on these risks have found conflicting results. In the present study, we investigate the MICA expression and serum MICA (sMICA) as well as the MICA antibodies (anti-MICA) in serum of recipients during acute rejection (AR) in a rat-to-mouse cardiac transplantation model., Methods: Construct rat-to-mouse concordant cardiac transplantation models, histological examination of the heart in recipients during AR at 2-6 hours time point was done. We then studied the MICA gene expression of the heart in recipients during AR at 2-6 hours time point by western blot and RT-PCR assay. We latter studied the anti-MICA and sMICA levels in serum of recipients during AR at 2-6 hours time point by Flow cytometry and ELISA measurement., Results: We found that Lewis rat hearts transplanted into BALB/c mice developed typical AR in 6 days. The level of severity of xenograft rejection from 2 d to 6 d was increased in a time-dependant way. MICA protein and MICA mRNA was also increased in time-dependant way and reached the highest value at 6 h. The prevalence of anti-MICA was significantly higher among those with severe acute rejection. However, sMICA was significantly increased during AR at 2 hours, then gradually decreased, and reached the lowest value at 6 h., Conclusions: MICA expression in recipients' heart and anti-MICA antibodies in recipients' sera may associated with high risk of AR in rat-to-mouse transplantation. sMICA showed a negative association with acute rejection and may be a good predictor of heart transplant outcomes.