mTORC2 inhibition reduces tumor burden via STAT1 activation and enhanced response to anti-PD-L1 therapy

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Melanoma treatment advances have not fully addressed response rates.
• Interferon pathway activation aids immune recognition but can cause immune exhaustion.
• Targeting Rictor in myeloid cells is a potential therapeutic strategy.

Purpose of the Study:

• To investigate the role of myeloid Rictor in melanoma immune response.
• To explore the therapeutic potential of targeting the Rictor-AKT axis in melanoma.

Main Methods:

• Myeloid-specific Rictor deletion in a mouse melanoma model.
• Analysis of STAT1 signaling and PD-L1 expression.
• Assessment of IFN-γ-activated macrophages on melanoma growth in organoids.
• In vivo combination therapy with AKT inhibition and anti-PD-L1.
• Investigation of IFN-γ, IGF-1, and STAT1 interactions.

Main Results:

• Myeloid Rictor deletion enhanced STAT1 signaling and reduced PD-L1.
• IFN-γ-activated macrophages inhibited melanoma growth.
• Combined AKT inhibition and anti-PD-L1 therapy suppressed tumor progression.
• IFN-γ downregulated IGF-1, dampening STAT1 activation; IGF-1 supplementation reduced STAT1 activation.

Conclusions:

• Targeting the Rictor-AKT axis offers a dual benefit: enhancing pro-inflammatory signals and decreasing immunosuppressive factors (PD-L1, IGF-1).
• AKT inhibitors show promise for improving immune checkpoint therapy efficacy in melanoma.