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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]

The COVID-19 global pandemic and high mortality rates necessitate the development of diagnostic and prognostic tools, as well as expanding testing capacity. Existing methods for detecting and characterizing SARS-CoV-2 infection are typically based on viral genome detection or measuring COVID-19-specific antibody levels. Despite their value, these methods are unable to predict disease outcomes in patients. Given the critical role of innate immune cells, particularly natural killer (NK) cells, in antiviral defense, this study sought to determine the prognostic value of serum secretory MHC class I polypeptide–related sequence A (sMICA) levels as an essential ligand for the NKG2D receptor, the master regulator of NK cell development and responsiveness. Serum MICA levels were measured by ELISA assay. Sera (n = 60) from SARS-CoV-2 positive patients were collected, and disease severity was determined using clinical criteria. The patient group included 30 patients with mild disease and 30 severely ill patients, as well as 30 healthy controls. Our findings revealed that serum MICA levels were significantly higher in patients than in controls, especially in cases with severe complications (P <.0001). Higher serum MICA levels may be associated with respiratory failure in COVID-19 and may serve as a marker of clinical severity in patients infected with SARS-CoV-2, particularly when clinical manifestations are insufficient to make a confident prediction. Higher MICA levels may be associated with respiratory failure in COVID-19 infection. SMICA levels change with age, particularly for patients with severe COVID-19 disease. NKG2D ligands may have prognostic and therapeutic value for COVID-19 patients. [ABSTRACT FROM AUTHOR]

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

Abstract: Introduction: Rheumatoid arthritis (RA) is a clinically heterogeneous chronic inflammatory disorder characterized by synovitis leading to joint destruction. Both genetic and environmental factors are involved in the pathogenesis of RA. Significant dysregulation of NKG2D, an activating receptor of natural killer and certain autoreactive T cells as well as its ligand major histocompatibility complex class I chain–related gene A (MICA) has been implicated in perpetuating the pathology of RA. Since the genetic polymorphism in MICA gene (MICA‐129 met/val polymorphism at codon 129) is known to affect its binding affinity to NKG2D, we explored its influence on RA susceptibility and disease severity. Methods: The MICA‐129 met/val polymorphism was examined in 270 patients with RA and 232 healthy controls by TaqMan 5′‐nuclease assay. Serum soluble MICA (sMICA) was measured in a subset of 89 patients and 80 controls by enzyme‐linked immunosorbent assay. Results: We observed that the frequency of MICA‐129 val allele (73% vs. 65%, Pc = 0.006, odds ratio = 1.48, 95% CI = 1.12–1.95) was higher in patients than in controls. sMICA levels were significantly higher in patients with RA than in controls (P < 0.0001). sMICA levels were higher in patients with val/val genotype than in those with met/val or met/met genotype (P = 0.03). The MICA‐129 val/val genotype was associated with high titers of sMICA in patients with deforming RA phenotype (P = 0.02), suggesting a role in determination of severity of RA. Conclusion: MICA‐129 val/val genotype, associated with higher levels of circulating sMICA, may influence disease susceptibility and associate with increased severity of RA in south Indian Tamils. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer in women worldwide. In this study, we correlated the serum level of major histocompatibility complex class I-related chain A (sMICA) with expression and presentation of NKG2D receptors on NK cells among patients with breast cancer. Peripheral blood (PB) samples were collected from 49 healthy and 49 breast cancer patients before surgery and chemotherapy. The expression and presentation of NKG2D were assessed using qRT-PCR and flow cytometry, respectively. Furthermore, sMICA levels were determined using ELISA. In flow cytometry, whole blood samples were stained with anti-CD56/NKG2D/CD3 and the obtained results were analyzed using WinMDI software. In addition, SPSS software was used for statistical analysis of data. Significantly higher levels sMICA were detected in the sera of the majority of cancer patients in contrast to healthy volunteers ( P < 0.001). The expression and presentation of NKG2D receptor were significantly lower than those in healthy persons, and with an inverse correlation to sMICA and positively correlated with tumor stage. Our study showed that sMICA may have an important role in diminishing the expression and presentation of NKG2D receptor in breast cancer patients and proposes the notion that sMICA can be a target candidate for treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: This study analyses aspects of the immune system in prolactinoma and non-secreting pituitary adenoma. Serum soluble major histocompatibility complex class I-related chain A protein (sMICA) concentrations were measured by enzyme-linked immunosorbent assay. NKG2D-expressing natural killer and T cells were analyzed by flow cytometry. A correlation analysis was also performed to associate sMICA levels with NKG2D expression. The expression of MICA was examined in specific tissues by use of the reverse transcription-polymerase chain reaction. A significant amount of sMICA was detected in the serum of nearly all patients. We found decreased percentage and mean fluorescence intensity of NKG2D-expressing natural killer and T cells from patients with prolactinoma and non-secreting pituitary adenoma compared to those from healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing cells. The immune-escape of pituitary adenoma is related to the down-regulation of NKG2D and the up-regulation of its ligand MICA. [Copyright &y& Elsevier]

Ataxia-telangiectasia (A-T) is a multisystem disorder caused by biallelic pathogenic variants in the gene encoding A-T mutated (ATM) kinase, a master regulator of the DNA damage response (DDR) pathway. Most A-T patients show cellular and/or humoral immunodeficiency that has been associated with cancer risk and reduced survival, but NK cells have not been thoroughly studied. Here we investigated NK cells of A-T patients with a special focus on the NKG2D receptor that triggers cytotoxicity upon engagement by its ligands (NKG2DLs) commonly induced via the DDR pathway on infected, transformed, and variously stressed cells. Using flow cytometry, we examined the phenotype and function of NK cells in 6 A-T patients as compared with healthy individuals. NKG2D expression was evaluated also by western blotting and RT-qPCR; plasma soluble NKG2DLs (sMICA, sMICB, sULBP1, ULBP2) were measured by ELISA. Results showed that A-T NK cells were skewed towards the CD56neg anergic phenotype and displayed decreased expression of NKG2D and perforin. NKG2D was reduced at the protein but not at the mRNA level and resulted in impaired NKG2D-mediated cytotoxicity in 4/6 A-T patients. Moreover, in A-T plasma we found 24-fold and 2-fold increase of sMICA and sULBP1, respectively, both inversely correlated with NKG2D expression. Overall, NK cells are disturbed in A-T patients showing reduced NKG2D expression, possibly caused by persistent engagement of its ligands, that may contribute to susceptibility to cancer and infections and represent novel targets for therapeutic interventions. • The CD56neg NK-cell subset was expanded in A-T patients. • NK cells of A-T patients showed reduced NKG2D and perforin expression. • NKG2D down-regulation in A-T NK cells occurred post-transcriptionally. • Increased sMICA and sULBP1 levels in A-T plasma were inversely correlated with NKG2D+ NK cells. • NKG2D-mediated NK cell activation was impaired in 4/6 A-T patients. [ABSTRACT FROM AUTHOR]

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]