MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) is a key cancer therapy, but patient response prediction remains challenging.
• MET amplification is implicated in various cancers and can affect treatment efficacy.

Purpose of the Study:

• To investigate the impact of MET amplification on ICB response in lung cancer patients.
• To elucidate the underlying mechanisms of ICB resistance driven by MET amplification.

Main Methods:

• Analysis of 81 lung cancer patients undergoing ICB treatment.
• Measurement of STING levels and T-cell infiltration in tumors.
• Deep single-cell RNA sequencing of over 20,000 immune cells.
• Mechanistic studies involving oncogenic MET signaling, UPF1, and STING expression.

Main Results:

• Patients with MET amplification exhibited resistance to ICB and poor progression-free survival.
• MET amplification was associated with decreased STING levels and reduced antitumor T-cell infiltration.
• Single-cell analysis revealed an immunosuppressive signature with exhausted NK cells and diminished CD8+ T-cells and NK-cells.
• Oncogenic MET signaling downregulates STING expression via UPF1 phosphorylation and 3'-UTR modulation.

Conclusions:

• MET amplification is a significant predictor of ICB resistance in lung cancer.
• Inhibiting MET can overcome ICB resistance mediated by MET amplification.
• Combination therapy with MET inhibitors and ICB shows promise for treating patients with MET-amplified lung cancer.