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

》》文章原文链接：Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR-Mutant Non-Small Cell Lung Cancer.

》》Journal：CANCER RESEARCH 

》》相关产品：Selumetinib (AZD6244) (SJ-MX0232)

》》产品引用描述：

》》Abstract：

Mutant EGFR is a common driver of non-small cell lung cancer (NSCLC). Although mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of patients with EGFR-mutant NSCLC 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 by promoting the expression of PD-L2 through reduced ubiquitination of c-MYC, and mutant EGFR cooperating to upregulate c-MYC and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced antitumor 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 tumor immune microenvironment of EGFR/CDKN2A co-mutant tumors and enhanced the antitumor 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. Significance: Upregulation of c-MYC driven by co-mutation of CDKN2A and EGFR increases PD-L2 to abrogate CD8+ T-cell activity in lung cancer, which confers sensitivity to PD-L2 blockade in combination with tyrosine kinase inhibitors.

》》部分实验数据展示：

Figure 5. F and G, T-cell–mediated tumor cell killing assay of LLC-Em cells. Cells were treated with or without anti–PD-L2 antibody, were given osimertinib (1 μmol/L), selumetinib (1 μmol/L), and osimertinib + selumetinib, respectively, and then cocultured with activated T cells for 72 hours. The remaining viable cells were stained with crystal violet. IFNγ secreted by CD8+ T cells was analyzed by flow cytometry.