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

ABSTRACT: Patients with metastatic high grade serous ovarian carcinoma (HGSOC) are often unresponsive to immunotherapies due to a hostile tumor microenvironment (TME). To identify the main drivers of immunosuppression, we performed an all-human functional screen of 4,292 druggable small molecules in the presence of malignant ascites from patients with HGSOC. Salt-inducible kinases (SIK) emerged as top targets that block human T cell antitumor activity. We saw that when cultured with cell-free patient ascites, primary human T cells express high levels of SIK. Administration of SIK inhibitors, YKL-05-099 or ARN-3236, consistently demonstrated therapeutic efficacy and survival advantages in syngeneic mouse models of resistant HGSOC. The encouraging outcomes from pharmaceutical inhibition of SIK were recapitulated by genetic depletion of Sik2/Sik3 in immunocompetent mice bearing HGSOC. In contrast, SIK inhibition in T cell-depleted hosts was ineffective, establishing T cell-centered antitumor immunity as the primary mechanism of action. Mechanistically, bulk transcriptomic analysis of tumor cells from SIK inhibitor-treated mice showed reduced disease progression along with upregulation of interferon-stimulated genes, while single-cell transcriptomic analysis of matched immune TME populations demonstrated increased infiltration of CD8 and CD4 T cells with enhanced cytotoxicity and effector cytokine function. Molecular studies in primary T cells identified in vivo target genes responsible for SIK-induced dysfunction including upregulation of TXNIP (Thioredoxin- Interacting Protein) and ZFP36L2 (ZFP36 Ring Finger Protein Like 2), negative regulators of effector cell metabolism and IFN-g cytokine production. We also observed downregulation of LYST and VPS37B, critical in cytotoxic granzyme biogenesis and trafficking. In contrast to PD-1 blockade alone that does not improve survival, combination of SIK inhibitors with immune checkpoint blockers significantly increased survival of mice with HGSOC. While T cells are the essential targets of SIK inhibitors, we noted that SIK inhibition boosted innate immunity including enhancing antigen presentation by dendritic cells. Spatial proteomic analysis (CODEX) in the presence of SIK inhibition further revealed a shift from immunosuppressive to immunostimulatory cellular neighborhoods. Our studies identify SIK as a key driver of immunosuppression in HGSOC. Treatment with SIK inhibitor alone or combined with PD-1 blockade may increase the survival of patients with ovarian cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE273961 | GEO | 2026/03/31

REPOSITORIES: GEO