Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Lung squamous carcinoma (LUSC) lacks targeted therapies unlike lung adenocarcinoma.
• Current immunotherapies show limited efficacy in LUSC.
• The role of the mTORC2 signaling pathway in LUSC immunity is unexplored.

Purpose of the Study:

• To investigate the mTORC2 signaling pathway as a therapeutic target in LUSC.
• To determine the impact of mTORC2 targeting on anti-tumor immune responses in LUSC.
• To explore the relationship between mTORC2, hypoxia, and immune evasion in LUSC.

Main Methods:

• Analysis of genetic alterations in LUSC patient tumors.
• In vivo studies using mouse models of LUSC.
• Transcriptomic analysis of mTORC2-deficient LUSC cells.
• Measurement of lactate levels and tumor microenvironment acidity.
• Investigation of PSGL-1 expression and its dependence on HIF-2α.
• Assessment of CD8+ T cell activation and response to anti-VISTA immunotherapy.

Main Results:

• Genetic alterations in the mTORC2 pathway are prevalent in LUSC.
• Targeting mTORC2 inhibits LUSC tumor growth in mouse models.
• mTORC2 deficiency reduces expression of glycolytic and hypoxia-related genes, lowering tumor acidity.
• mTORC2-deficient LUSC cells show decreased PSGL-1 expression via a HIF-2α-dependent mechanism.
• A positive correlation between HIF-2α and PSGL-1 exists in LUSC but not LUAD.
• mTORC2 loss enhances CD8+ T cell activation; anti-VISTA therapy is effective only with intact mTORC2.

Conclusions:

• The mTORC2 signaling pathway is a critical regulator of the tumor immune microenvironment in LUSC.
• Targeting the mTORC2/PSGL-1/VISTA axis presents a promising therapeutic strategy for LUSC.
• This approach may benefit patients unresponsive to current LUSC therapies.