Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-Type Non-Small Cell Lung Cancer

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Immune checkpoint inhibitors (ICIs) have advanced non-small cell lung cancer (NSCLC) treatment, but resistance limits efficacy in many patients.
• Understanding resistance mechanisms is crucial for improving ICI therapy outcomes in NSCLC.

Purpose of the Study:

• To investigate the role of neurotrophic tyrosine kinase receptor 1 (NTRK1) signaling in ICI resistance in NSCLC.
• To explore NTRK1 inhibition as a strategy to enhance ICI efficacy.

Main Methods:

• Analysis of overall survival and mutational profiles in 424 NSCLC patients treated with ICIs.
• In vivo studies using NSCLC mouse models with NTRK1 knockdown or entrectinib treatment.
• T-cell population analysis and RNA sequencing to assess immune cell infiltration and gene expression.

Main Results:

• Loss-of-function mutations in NTRK1 were associated with prolonged overall survival in NSCLC patients treated with ICIs.
• NTRK1 pathway suppression enhanced ICI efficacy in preclinical NSCLC models.
• Decreased NTRK1 signaling led to enrichment of T cells and M1-like macrophages, mediated by increased complement C3 expression.

Conclusions:

• NTRK1 signaling regulates tumor-immune cell interactions within the tumor microenvironment.
• Inhibiting NTRK1 can sensitize NSCLC to immunotherapy by boosting complement C3-mediated immune responses.
• Targeting NTRK1 offers a potential strategy to overcome ICI resistance in NSCLC patients with wild-type NTRK1.