Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Oncogenic drivers like EGFR, KRAS, and ALK are key in lung cancer.
• The tumor microenvironment's immune landscape is crucial for cancer progression.
• Immune checkpoint inhibitors (e.g., PD-1, PD-L1) show clinical efficacy, suggesting immune suppression in lung cancer.

Purpose of the Study:

• To investigate the role of the AKT-mTOR pathway in regulating PD-L1 expression.
• To determine if mTOR activation correlates with PD-L1 expression in human lung cancers.
• To evaluate the therapeutic potential of combining mTOR inhibitors with PD-1 blockade.

Main Methods:

• In vitro and in vivo experiments assessing PD-L1 regulation by the AKT-mTOR pathway.
• Analysis of PD-L1 and mTOR expression in human lung adenocarcinoma and squamous cell carcinoma tissues.
• Treatment of syngeneic and genetically engineered mouse models of lung cancer with an mTOR inhibitor and a PD-1 antibody.

Main Results:

• AKT-mTOR pathway activation was shown to tightly regulate PD-L1 expression.
• Both oncogenic and IFNγ-induced PD-L1 expression were dependent on mTOR.
• Membranous PD-L1 expression significantly correlated with mTOR activation in human lung cancers.
• Combined mTOR inhibition and PD-1 blockade decreased tumor growth in mouse models.
• Combination therapy increased tumor-infiltrating T cells and decreased regulatory T cells.

Conclusions:

• Oncogenic activation of the AKT-mTOR pathway promotes immune escape by upregulating PD-L1.
• Targeting the AKT-mTOR pathway in combination with PD-1 blockade represents a potential therapeutic strategy for lung cancer.