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.

中文翻译：

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CDKN2A 缺失增强免疫治疗对 EGFR 突变非小细胞肺癌的疗效


突变的表皮生长因子受体 （EGFR） 是非小细胞肺癌 （NSCLC） 的常见驱动因素。虽然据报道 EGFR 突变会限制免疫治疗的疗效，但 EGFR 突变 NSCLC 患者亚群受益于免疫检查点抑制剂治疗。更好地了解致癌驱动基因中同时发生的基因组改变如何影响免疫治疗效果，可能有助于更全面地了解癌症异质性并确定反应的生物标志物。在这里，我们研究了 EGFR 突变肺癌模型中频繁 EGFR 共突变的影响，并确定了 CDKN2A 的功能丧失突变是体外和体内抗 PD-1 治疗的潜在致敏剂。从机制上讲，CDKN2A 缺失通过减少 c-Myc 的泛素化促进 PD-L2 的表达，从而影响肿瘤免疫微环境 （TIME） 的组成，而突变的 EGFR 通过激活 MAPK 通路合作上调 c-Myc 和 PD-L2。阻断 PD-L2 诱导的 EGFR/CDKN2A 共突变肺癌中 CD8+ T 细胞介导的抗肿瘤免疫反应。重要的是，小分子 PD-L2 抑制剂十一烯酸锌重塑了 EGFR/CDKN2A 共突变肿瘤的时间，并增强了 EGFR-酪氨酸激酶抑制剂的抗肿瘤功效。总的来说，这些结果将 EGFR/CDKN2A 共突变确定为 NSCLC 的一种独特亚型，其对免疫检查点阻断表现出优异的敏感性，并揭示了治疗该 NSCLC 亚型的潜在联合治疗策略。