Inhibition of salt inducible kinases reprograms T cells and antitumor immunity in ovarian cancer

Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, while SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant HGSOC, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival.

We identified a major role of T cell-intrinsic SIK2/3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-g, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.