دورية أكاديمية
أعرض في EDS

Enhanced T cell effector activity by targeting the Mediator kinase module.

التفاصيل البيبلوغرافية
العنوان: Enhanced T cell effector activity by targeting the Mediator kinase module.
المؤلفون: Freitas KA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Belk JA; Department of Computer Science, Stanford University, Stanford, CA, USA., Sotillo E; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Quinn PJ; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Ramello MC; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Malipatlolla M; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Daniel B; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Sandor K; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Klysz D; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Bjelajac J; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Xu P; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Burdsall KA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Tieu V; Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA., Duong VT; Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA., Donovan MG; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Weber EW; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Majzner RG; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Division of Pediatric Hematology/Oncology and Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Espinosa JM; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Satpathy AT; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Mackall CL; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Division of Pediatric Hematology/Oncology and Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Division of Blood and Marrow Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
المصدر: Science (New York, N.Y.) [Science] 2022 Nov 11; Vol. 378 (6620), pp. eabn5647. Date of Electronic Publication: 2022 Nov 11.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
أسماء مطبوعة: Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
مواضيع طبية MeSH: Mediator Complex*/genetics , T-Lymphocytes*/immunology , Receptors, Chimeric Antigen* , Cyclin C*/genetics , Neoplasms*/immunology , Neoplasms*/therapy, Humans ; Cyclin-Dependent Kinase 8/metabolism ; Cyclin-Dependent Kinases/metabolism ; Transcription Factors/genetics ; Genome-Wide Association Study ; Genetic Testing ; Immunotherapy, Adoptive
مستخلص: T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC , components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12 -deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.
التعليقات: Comment in: Science. 2022 Nov 11;378(6620):598. doi: 10.1126/science.adf0546. (PMID: 36356156)
Comment in: Nat Rev Drug Discov. 2023 Jan;22(1):16. doi: 10.1038/d41573-022-00196-x. (PMID: 36446914)
Comment in: Nat Rev Immunol. 2023 Jan;23(1):6. doi: 10.1038/s41577-022-00817-x. (PMID: 36470970)
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معلومات مُعتمدة: RM1 HG007735 United States HG NHGRI NIH HHS; 75N92020D00005 United States HL NHLBI NIH HHS; T32 GM145402 United States GM NIGMS NIH HHS; R01 AI150305 United States AI NIAID NIH HHS; 75N93022D00005 United States AI NIAID NIH HHS; 75N99020D00005 United States OF ORFDO NIH HHS; U54 CA232568 United States CA NCI NIH HHS; U01 CA260852 United States CA NCI NIH HHS; S10 RR025518 United States RR NCRR NIH HHS; 75N93023D00005 United States AI NIAID NIH HHS; R35 CA209919 United States CA NCI NIH HHS; 75N95020D00005 United States DA NIDA NIH HHS
المشرفين على المادة: EC 2.7.11.22 (Cyclin-Dependent Kinase 8)
EC 2.7.11.22 (Cyclin-Dependent Kinases)
0 (Mediator Complex)
0 (Transcription Factors)
0 (Receptors, Chimeric Antigen)
0 (MED12 protein, human)
0 (CCNC protein, human)
0 (Cyclin C)
تواريخ الأحداث: Date Created: 20221110 Date Completed: 20221118 Latest Revision: 20240626
رمز التحديث: 20240626
مُعرف محوري في PubMed: PMC10335827
DOI: 10.1126/science.abn5647
PMID: 36356142
قاعدة البيانات: MEDLINE
الوصف
تدمد:1095-9203
DOI:10.1126/science.abn5647