ULK1 as a novel therapeutic target to enhance immune checkpoint therapies against melanoma

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Renu Goel  

LAB HEAD: Leonidas C. Platanias

PROVIDER: PXD035347 | Pride | 2023-02-02

REPOSITORIES: Pride