Targeting ULK1 Decreases IFNg-Mediated Resistance to Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors (ICI) have transformed the ULK1 reduces expression of IFNg-induced immunosuppressive treatment of melanoma. However, the majority of patients have genes. ULK1 binds IRF1 in the nuclear compartment of melanoma primary or acquired resistance to ICIs, limiting durable responses cells, controlling its binding to the programmed death-ligand and patient survival. IFNg signaling and the expression of IFNg-1 promoter region. In addition, pharmacologic inhibition of ULK1 stimulated genes correlate with either response or resistance to ICIs, in combination with anti-programmed cell death protein 1 therapy in a context-dependent manner. While IFNg-inducible immunosfurther reduces melanoma tumor growth in vivo. Our data suggest timulatory genes are required for response to ICIs, chronic IFNg that targeting ULK1 represses IFNg-dependent immunosuppressignaling induces the expression of immunosuppressive genes, sion. These findings support the combination of ULK1 drug-promoting resistance to these therapies. Here, we show that high targeted inhibition with ICIs for the treatment of patients with levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in melanoma to improve response rates and patient outcomes. patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive Implications: This study identifies ULK1, activated downstream genes, with minimal effects on the expression of immunostimulaof IFNg signaling, as a druggable target to overcome resistance tory genes. In contrast, genetic or pharmacologic inhibition of mechanisms to ICI therapy in metastatic melanoma.