CD47 blockade improves the therapeutic effect of osimertinib in non-small cell lung cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Osimertinib (OSI) is a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC).
• EGFR inhibitors can modulate immune checkpoints, potentially limiting their long-term efficacy.
• Understanding these immune interactions is crucial for developing combination therapies.

Purpose of the Study:

• To investigate the effect of OSI on CD47 expression in EGFR-mutant NSCLC cells.
• To evaluate the efficacy of combining OSI with an anti-CD47 antibody.
• To explore the underlying mechanisms of this combination therapy.

Main Methods:

• EGFR-mutant NSCLC cell lines (HCC827, NCI-H1975) were treated with OSI.
• CD47 expression and NF-κB pathway activation were assessed.
• Combination therapy with OSI and anti-CD47 antibody was tested in vitro and in a HCC827 xenograft mouse model.
• Antibody-dependent cellular phagocytosis (ADCP) and immune checkpoint markers (calreticulin, PD-L1) were analyzed.

Main Results:

• OSI treatment upregulated CD47 expression via the NF-κB pathway in NSCLC cells.
• Combination therapy with OSI and anti-CD47 antibody significantly enhanced phagocytosis, dependent on ADCP.
• CD47 knockout cells showed reversed phagocytosis enhancement.
• The combination therapy augmented OSI's anticancer effect in vivo and modulated "eat me"/"don't eat me" signals.

Conclusions:

• OSI treatment induces CD47 upregulation in EGFR-mutant NSCLC, presenting a potential therapeutic target.
• Combining OSI with anti-CD47 antibody enhances phagocytosis and antitumor activity.
• This combination strategy warrants further investigation for treating EGFR-mutant NSCLC.