Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR-Mutant Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Mutant epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) but can limit immunotherapy efficacy.
• A subset of NSCLC patients with EGFR mutations benefit from immune checkpoint inhibitors, suggesting complex interactions.
• Understanding co-occurring genomic alterations is crucial for deciphering cancer heterogeneity and identifying immunotherapy response biomarkers.

Purpose of the Study:

• To investigate the impact of frequent EGFR co-mutations on immunotherapy efficacy in EGFR-mutant lung cancer.
• To identify potential genomic alterations that sensitize EGFR-mutant NSCLC to anti-PD-1 treatment.
• To elucidate the underlying mechanisms by which co-mutations influence the tumor immune microenvironment and response to therapy.

Main Methods:

• Utilized EGFR-mutant lung cancer models to study the effects of co-mutations.
• Investigated the role of CDKN2A loss-of-function mutations in modulating anti-PD-1 treatment response in vitro and in vivo.
• Analyzed the impact of CDKN2A loss on tumor immune microenvironment composition, including PD-L2 expression and c-MYC ubiquitination.
• Examined the activation of the MAPK pathway in regulating c-MYC and PD-L2 expression in EGFR/CDKN2A co-mutant tumors.
• Assessed the efficacy of PD-L2 blockade and combination therapy with EGFR tyrosine kinase inhibitors.

Main Results:

• Loss-of-function mutation of CDKN2A was identified as a sensitizer to anti-PD-1 treatment in EGFR-mutant lung cancer models.
• CDKN2A loss promoted PD-L2 expression by reducing c-MYC ubiquitination, altering the tumor immune microenvironment.
• Mutant EGFR and CDKN2A loss cooperatively upregulated c-MYC and PD-L2 via MAPK pathway activation.
• Blocking PD-L2 induced CD8+ T cell-mediated antitumor immune responses in EGFR/CDKN2A co-mutated lung cancer.
• A small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the tumor immune microenvironment and enhanced EGFR tyrosine kinase inhibitor efficacy.

Conclusions:

• EGFR/CDKN2A co-mutation defines a distinct NSCLC subtype with heightened sensitivity to immune checkpoint blockade.
• Upregulation of c-MYC, driven by EGFR and CDKN2A co-mutation, increases PD-L2, which suppresses CD8+ T cell activity.
• PD-L2 blockade, particularly in combination with tyrosine kinase inhibitors, represents a promising therapeutic strategy for this NSCLC subtype.