Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Lung cancer, particularly non-small-cell lung carcinoma (NSCLC) with mutant EGFR, has high mortality rates.
• Current treatments like osimertinib show efficacy but face resistance and lack of immune response.
• EGFR-mutant NSCLC patients often cannot tolerate checkpoint inhibitors, limiting therapeutic options.

Purpose of the Study:

• To explore the combination of osimertinib with anti-HER3 monoclonal antibodies for treating EGFR-mutant NSCLC.
• To investigate the role of innate immunity and the cGAS-STING pathway in this combination therapy.
• To identify strategies to overcome resistance mechanisms and enhance anti-tumor immune responses.

Main Methods:

• In vivo studies in mice and in vitro co-culture experiments with bone marrow-derived macrophages and human PBMCs.
• Assessment of osimertinib-induced apoptosis, HER3 upregulation, macrophage infiltration, and cGAS-STING pathway activation.
• Utilized a lentivirally transduced STING activity biosensor to detect cGAMP production.

Main Results:

• Osimertinib induced tumor cell apoptosis and triggered IRE1α-dependent HER3 upregulation.
• Combination therapy increased macrophage infiltration and activated the cGAS-STING pathway in cancer cells and macrophages.
• Anti-HER3 antibodies mediated Fc receptor-dependent tumor elimination by macrophages.
• STING agonists further enhanced macrophage-mediated tumor destruction.

Conclusions:

• The combination of osimertinib and anti-HER3 antibodies engages a tumor non-autonomous mechanism involving cGAS-STING and innate immunity.
• This strategy holds potential to improve therapeutic options for advanced EGFR-mutant lung cancer.
• Further research into this combination could enhance treatment efficacy and overcome resistance mechanisms.