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

Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.