IMPS-45IDH MUTANT GLIOMAS ESCAPE NATURAL KILLER CELL IMMUNE SURVEILLANCE THROUGH DOWNREGULATION OF NKG2D LIGANDS
| العنوان: | IMPS-45IDH MUTANT GLIOMAS ESCAPE NATURAL KILLER CELL IMMUNE SURVEILLANCE THROUGH DOWNREGULATION OF NKG2D LIGANDS |
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| المؤلفون: | Paola Grandi, Nduka Amankulor, Xiaoran Zhang, Aparna Rao, Christopher P Deibert, Jason Kim, Paola Sette, Michael T. Lotze |
| المصدر: | Neuro-Oncology. 17:v123-v123 |
| بيانات النشر: | Oxford University Press (OUP), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, medicine.medical_treatment, Biology, medicine.disease, NKG2D, Molecular biology, Isotype, Natural killer cell, medicine.anatomical_structure, Cytokine, Oncology, Glioma, Blocking antibody, Gene expression, medicine, biology.protein, Neurology (clinical), Antibody, Abstracts from the 20th Annual Scientific Meeting of the Society for Neuro-Oncology |
| الوصف: | Mutations in isocitrate dehydrogenase 1 and 2 are common in gliomas. 50-80% of WHO II/III gliomas possess IDH1/IDH2 mutation. Methylation-related transcriptional repression is a feature of IDH mutant (IDHmut) tumors. Epigenetic repression of natural killer (NK) cell ligands is a common mechanism of immune escape in cancer, but it is unknown if this occurs in gliomas. We compared IDHmut and IDHwt tumor expression (z-score) and methylation (mean methylation score) data from the TCGA low-grade glioma database, and found two NKG2D ligands (ULBP1, ULBP3) that were downregulated (-0.47, p = 0.02; -1.28, p < 0.01) and hypermethylated (-0.31, p < 0.01; -0.15, p < 0.01) in IDHmut tumors. We validated this finding by measuring ULBP1 and ULBP3 gene expression in cells derived from IDHwt and IDHmut patients and found both genes were repressed in IDHmut cells (-0.85 fold expression, p = 0.01; -0.57 fold expression, p = 0.01). To determine whether repression of NKG2D ligand expression resulted in escape from NK recognition and specific lysis, we these cells with NK cells. We observed significantly (p = 0.03) reduced specific lysis of IDHmut cell (3.62%) as compared to IDHwt cells (24.13%). To determine NK activation, we measured inflammatory cytokine release in co-cultures, no basal release were detected in either tumor or NK monocultures. IDHmut co-cultures has significantly reduced IFN-g (82.08 pg/mL vs 250.1 pg/mL, p = 0.02) and TNF-a (151.2 pg/mL vs 650.2 pg/mL, p < 0.01) release compared to IDHwt co-cultures. To validate that IDHmut immune escape is NKG2D dependent, we blocked NKG2D binding using an antibody. Addition of isotype antibody did not significantly reduce specific lysis in IDHwt co-culture (10.40% vs 10.20%, p = 0.94). Addition of NKG2D blocking antibody to IDHwt significantly reduced specific lysis below isotype (3.34% vs 10.40%, p < 0.01). In conclusion, we were able to demonstrate that IDH mutant gliomas are able to escape from NK immune surveillance through repression of NKG2D ligand expression. |
| تدمد: | 1523-5866 1522-8517 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7c8377769beccc5141bc0ca6799b6f4Test https://doi.org/10.1093/neuonc/nov217.44Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d7c8377769beccc5141bc0ca6799b6f4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15235866 15228517 |
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