RSK1 reprograms the ubiquitin pathway to promote immune suppression

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) shows promise in cancer therapy, but intrinsic tumor resistance limits its effectiveness for many patients.
• Understanding the molecular mechanisms of tumor-intrinsic immune suppression is crucial for improving ICB efficacy.

Purpose of the Study:

• To identify novel regulators of tumor-intrinsic immune suppression that affect ICB response.
• To elucidate the molecular pathway through which RNF19A suppresses the immune response.

Main Methods:

• In vivo genetic screens to identify immune suppressors.
• Biochemical assays to determine protein interactions and enzymatic activities (ubiquitination, phosphorylation).
• Xenograft mouse models and analysis of patient tumor tissues.

Main Results:

• RNF19A was identified as a novel immune suppressor that impairs ICB efficacy by ubiquitinating cGAS, thereby inhibiting type I interferon production.
• UBE2L6, an ISG15-conjugating enzyme, was found to be the primary E2 enzyme for RNF19A-mediated cGAS ubiquitination.
• RSK1 phosphorylates UBE2L6, switching its function from ISG15ylation to ubiquitination, thus promoting immune suppression.
• Inhibition of RSK1 or UBE2L6 phosphorylation enhanced anti-tumor immune responses in preclinical models.
• Elevated UBE2L6 levels and phosphorylation in patient tissues correlated with poor immune infiltration and reduced response to immunotherapy and radiation therapy.

Conclusions:

• RSK1-mediated phosphorylation of UBE2L6 converts it into a ubiquitin E2 enzyme, facilitating RNF19A-driven cGAS ubiquitination and leading to tumor-intrinsic immune suppression.
• This pathway represents a critical mechanism of resistance to ICB and suggests RSK1 and UBE2L6 as potential therapeutic targets to overcome resistance and improve cancer treatment outcomes.