Abstract
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 IL2Rintermediate 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. Lowdose 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1393-1405 |
| Number of pages | 13 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 21 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 6 Sept 2022 |
Bibliographical note
Funding Information:J.G. Aerts reports grants and personal fees from BMS, personal fees from MSD and Eli Lilly, grants and personal fees from Amphera, personal fees and other support from BIOCAD, and personal fees from Takeda outside the submitted work; as well as reports a patent for tumor lysate licensed to Amphera and Biomarker for IO licensed to Pamgene. No disclosures were reported by the other authors.
Publisher Copyright:
© 2022 American Association for Cancer Research.
