Terminal T-cell exhaustion poses a significant barrier to effective anti-cancer 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 IL-2 receptor (IL-2R) - STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL-2R-intermediate Janus kinase (JAK) 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) which potently inhibited STAT5-phosphorylation in vitro. Whereas pulsed high-dose JAK3i administration inhibited anti-tumor 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 to both monotherapies alone. Collectively, these results identify JAK3 as a novel and promising target for combination immunotherapy.

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