| Autor: |
Floris Dammeijer, Mandy van Gulijk, Larissa Klaase, Menno van Nimwegen, Rachid Bouzid, Robin Hoogenboom, Maria E. Joosse, Rudi W. Hendriks, Thorbald van Hall, Joachim G. Aerts |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Molecular Cancer Therapeutics, 21(9), 1393-1405. AMER ASSOC CANCER RESEARCH |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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