CDKN2A 缺失可增强表皮生长因子受体突变非小细胞肺癌免疫疗法的疗效

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-11-08 DOI:10.1158/0008-5472.can-24-1817
Simeng Wang, Jia-Cheng Lai, Yu Li, Chengfang Tang, Jiajia Lu, Min Han, Xianjiang Ye, Lina Jia, Wei Cui, Jingyu Yang, Chunfu Wu, Lihui Wang
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引用次数: 0

摘要

表皮生长因子受体(EGFR)突变是非小细胞肺癌(NSCLC)的常见诱因。据报道,突变表皮生长因子受体限制了免疫疗法的疗效,但也有一部分表皮生长因子受体突变的非小细胞肺癌患者受益于免疫检查点抑制剂的治疗。如果能更好地了解致癌驱动基因中同时出现的基因组改变如何影响免疫疗法的疗效,就能更全面地了解癌症的异质性并确定反应的生物标志物。在这里,我们研究了表皮生长因子受体(EGFR)突变肺癌模型中频繁发生的EGFR共突变的影响,并发现CDKN2A功能缺失突变是体外和体内抗PD-1治疗的潜在增敏剂。从机理上讲,CDKN2A的缺失通过减少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,而突变的表皮生长因子受体则通过激活MAPK通路协同上调c-Myc和PD-L2。在表皮生长因子受体/CDKN2A共同突变的肺癌中,阻断PD-L2可诱导CD8+ T细胞介导的抗肿瘤免疫反应。重要的是,小分子 PD-L2 抑制剂十一烯酸锌能重塑表皮生长因子受体/CDKN2A 共突变肿瘤的 TIME,增强表皮生长因子受体酪氨酸激酶抑制剂的抗肿瘤疗效。总之,这些结果确定了表皮生长因子受体/CDKN2A共突变是一种独特的NSCLC亚型,它对免疫检查点阻断剂显示出更高的敏感性,并揭示了治疗这种NSCLC亚型的潜在联合治疗策略。
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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.
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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