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Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors

Sarah E Fenton1,2, Markella Zannikou1,2, Liliana Ilut1

  • 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.

Molecular Cancer Research : MCR
|December 27, 2022
PubMed

Insights

Targeting Unc-51 like kinase 1 (ULK1) may overcome resistance to immune checkpoint inhibitors (ICI) in melanoma. Inhibiting ULK1 reduces immunosuppressive genes and enhances ICI therapy effectiveness, improving patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, but resistance remains a significant challenge.
  • Interferon-gamma (IFNγ) signaling plays a dual role, promoting response or resistance to ICIs depending on context.
  • Chronic IFNγ signaling can induce immunosuppressive genes, contributing to therapeutic resistance.

Purpose of the Study:

  • To investigate the role of Unc-51 like kinase 1 (ULK1) in IFNγ-mediated immunosuppression in melanoma.
  • To determine if ULK1 is a druggable target to overcome resistance to ICIs in melanoma.

Main Methods:

  • Correlating ULK1 levels with patient survival in melanoma.
  • Overexpressing or inhibiting ULK1 in melanoma cells to assess effects on IFNγ-stimulated genes.
  • Investigating ULK1's interaction with IRF1 and its role in regulating the PD-L1 promoter.
  • Evaluating the efficacy of ULK1 inhibition combined with anti-PD-1 therapy in vivo.

Main Results:

  • High ULK1 levels correlate with poor melanoma patient survival.
  • ULK1 overexpression enhances IFNγ-induced immunosuppressive genes while minimally affecting immunostimulatory genes.
  • ULK1 inhibition reduces IFNγ-induced immunosuppressive gene expression.
  • ULK1 interacts with IRF1, influencing its binding to the PD-L1 promoter.
  • Combined ULK1 inhibition and anti-PD-1 therapy reduced tumor growth in vivo.

Conclusions:

  • ULK1 is activated downstream of IFNγ signaling and promotes melanoma immunosuppression.
  • Targeting ULK1 represents a novel strategy to overcome resistance to ICIs in melanoma.
  • Combining ULK1 inhibition with ICIs may improve treatment response and outcomes for melanoma patients.

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