دورية أكاديمية
Stat5 opposes the transcription factor Tox and rewires exhausted CD8 + T cells toward durable effector-like states during chronic antigen exposure.
| العنوان: | Stat5 opposes the transcription factor Tox and rewires exhausted CD8 + T cells toward durable effector-like states during chronic antigen exposure. |
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| المؤلفون: | Beltra JC; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA., Abdel-Hakeem MS; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt., Manne S; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zhang Z; Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA., Huang H; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA., Kurachi M; Department of Molecular Genetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan., Su L; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Picton L; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Ngiow SF; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Muroyama Y; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Casella V; Infection Biology Laboratory, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Huang YJ; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Giles JR; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA., Mathew D; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA., Belman J; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Klapholz M; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Decaluwe H; Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada., Huang AC; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Berger SL; Department of Cell and Developmental Biology, Penn Epigenetics Institute, Perelman School of Medicine, Philadelphia, PA 19104, USA., Garcia KC; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA., Wherry EJ; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. Electronic address: wherry@pennmedicine.upenn.edu. |
| المصدر: | Immunity [Immunity] 2023 Dec 12; Vol. 56 (12), pp. 2699-2718.e11. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge, MA : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1994- |
| مواضيع طبية MeSH: | CD8-Positive T-Lymphocytes* , Transcription Factors*/genetics, Interleukin-2 ; Gene Expression Regulation ; Programmed Cell Death 1 Receptor/metabolism |
| مستخلص: | Rewiring exhausted CD8 + T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Tex prog ) to intermediate (Tex int ) and terminal (Tex term ) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Tex int cell formation and re-instigated partial effector biology during this Tex prog -to-Tex int cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8 + T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Tex int cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states. Competing Interests: Declaration of interests A.C.H. performed consulting work for Immunai and receives research funding from B.M.S and Merck. K.C.G. is the founder of Synthekine. E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supported the study. E.J.W. is an advisor for Coherus, Danger Bio, Marengo, Janssen, NewLimit, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, Synthekine. E.J.W. is a founder of Arsenal Biosciences. (Copyright © 2023 Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | P01 CA210944 United States CA NCI NIH HHS; R35 CA263922 United States CA NCI NIH HHS; U19 AI117950 United States AI NIAID NIH HHS; P50 CA261608 United States CA NCI NIH HHS; R01 AI155577 United States AI NIAID NIH HHS; K08 CA230157 United States CA NCI NIH HHS; U19 AI082630 United States AI NIAID NIH HHS; P50 CA174523 United States CA NCI NIH HHS; R01 AI115712 United States AI NIAID NIH HHS; R01 CA273018 United States CA NCI NIH HHS; P30 CA016520 United States CA NCI NIH HHS; R01 AI051321 United States AI NIAID NIH HHS; P01 AI108545 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: CD8(+) T cell; IL-2; PD-1 blockade; Stat5; Tex intermediate; Tox; epigenetic reprogramming; exhaustion; orthogonal IL-2:IL2Rβ |
| المشرفين على المادة: | 0 (Transcription Factors) 0 (Interleukin-2) 0 (Programmed Cell Death 1 Receptor) |
| تواريخ الأحداث: | Date Created: 20231213 Date Completed: 20231216 Latest Revision: 20240726 |
| رمز التحديث: | 20240726 |
| مُعرف محوري في PubMed: | PMC10752292 |
| DOI: | 10.1016/j.immuni.2023.11.005 |
| PMID: | 38091951 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4180 |
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| DOI: | 10.1016/j.immuni.2023.11.005 |