دورية أكاديمية
Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy.
| العنوان: | Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy. |
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| المؤلفون: | Dammeijer F; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.; Erasmus MC Cancer Institute, Erasmus MC, University Medical Center Rotterdam, the Netherlands., van Gulijk M; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.; Erasmus MC Cancer Institute, Erasmus MC, University Medical Center Rotterdam, the Netherlands., Klaase L; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands., van Nimwegen M; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands., Bouzid R; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands., Hoogenboom R; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands., Joosse ME; Erasmus MC Cancer Institute, Erasmus MC, University Medical Center Rotterdam, the Netherlands., Hendriks RW; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands., van Hall T; Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, the Netherlands., Aerts JG; Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.; Erasmus MC Cancer Institute, Erasmus MC, University Medical Center Rotterdam, the Netherlands. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2022 Sep 06; Vol. 21 (9), pp. 1393-1405. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Immunotherapy* , Janus Kinase 3*/antagonists & inhibitors , Neoplasms*/therapy , T-Lymphocytes*/immunology, Animals ; Mice ; Phosphorylation ; Receptors, Interleukin-2/metabolism ; STAT5 Transcription Factor/metabolism |
| مستخلص: | Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited antitumor T-cell effector function, low-dose chronic JAK3i significantly improved T-cell responses and decreased tumor load in mouse models of solid cancer. Low-dose JAK3i combined with cellular and peptide vaccine strategies further decreased tumor load compared with both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy. (©2022 American Association for Cancer Research.) |
| المشرفين على المادة: | 0 (Receptors, Interleukin-2) 0 (STAT5 Transcription Factor) EC 2.7.10.2 (Jak3 protein, mouse) EC 2.7.10.2 (Janus Kinase 3) |
| تواريخ الأحداث: | Date Created: 20220622 Date Completed: 20220908 Latest Revision: 20221012 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1158/1535-7163.MCT-21-0943 |
| PMID: | 35732501 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-21-0943 |