Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Luoyang Cancer Clinical Diagnosis and treatment Research Center, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
Bioengineered. 2022 May;13(5):11577-11592. doi: 10.1080/21655979.2022.2069328.
Immunotherapy significantly improves the prognosis of advanced lung cancer. It has become an important treatment option for advanced lung cancer. However, there remain many limitations in clinical treatment, and only a small portion of patients can benefit from immunotherapy. Our study aimed to identify markers that can precisely forecast the efficacy of immunotherapy in patients. We analyzed a non-small-cell lung cancer (NSCLC) immune checkpoint inhibitor (ICI) cohort (n=240). We used this discovery cohort to identify CNVs in genes associated with immunotherapy. We further analyzed immune biomarkers and immune infiltration in The Cancer Genome Atlas (TCGA)-NSCLC cohort and the Gene Expression Omnibus (GEO) cohorts. By analyzing an ICI dataset from MSKCC, we found that progression-free survival (PFS) was improved after UBE3A deletion (UBE3A-del). The analysis results showed that UBE3A-del had higher immunocyte infiltration levels and higher expression levels of immune checkpoint biomarkers and affected the enrichment levels of immune signaling pathways. Our results suggest that UBE3A-del can be used as a predictive biomarker of NSCLC to screen for NSCLC patients who may benefit from ICI therapy. NSCLC: Non-small cell lung cancer; CNV: Copy number variation; ICIs: Immune checkpoint inhibitors; TCGA: The cancer genome atlas; GEO: Gene expression omnibus; GSEA: Gene set enrichment; PFS: Progression-free survival; OS: Overall survival; TMB: Tumor mutational burden; CTLA-4: Cytotoxic T lymphocyte antigen 4; PD-(L)1: Programmed cell death (ligand) 1; MSI: Microsatellite instability; dMMR: DNA mismatch repair; SCNAs: Somatic copy number alterations; TME: Tumor microenvironment; MSK-IMPACT: The Memorial Sloan Kettering-Integrated Mutation Profilng of Actionable; Cancer Targets; FDA: Food and Drug Administration; WES: Whole-exome sequencing; SNP: Single Nucleotide Polymorphisms; FDR: False discovery rate; DCR: Disease control rate; DDR: DNA damage response and repair; MDSCs: Myeloid-derived suppressor cells; FAO: Fatty acid oxidation.
免疫疗法显著改善了晚期肺癌的预后，已成为晚期肺癌的重要治疗选择。然而，临床治疗仍存在诸多局限，仅有一小部分患者能从免疫治疗中获益。本研究旨在寻找能准确预测免疫治疗疗效的标志物。我们分析了一个非小细胞肺癌（NSCLC）免疫检查点抑制剂（ICI）队列（n=240），利用该发现队列鉴定与免疫治疗相关的基因中的拷贝数变异（CNVs）。我们进一步在 TCGA-NSCLC 队列和 GEO 队列中分析免疫标志物和免疫浸润。通过分析 MSKCC 的 ICI 数据集，我们发现 UBE3A 缺失（UBE3A-del）后无进展生存期（PFS）得到改善。分析结果显示，UBE3A-del 具有更高的免疫细胞浸润水平，更高的免疫检查点标志物表达水平，并影响免疫信号通路的富集水平。我们的结果表明，UBE3A-del 可作为 NSCLC 的预测生物标志物，筛选可能从 ICI 治疗中获益的 NSCLC 患者。 NSCLC：非小细胞肺癌；CNV：拷贝数变异；ICI：免疫检查点抑制剂；TCGA：癌症基因组图谱；GEO：基因表达综合数据库；GSEA：基因集富集分析；PFS：无进展生存期；OS：总生存期；TMB：肿瘤突变负荷；CTLA-4：细胞毒性 T 淋巴细胞相关抗原 4；PD-（L）1：程序性细胞死亡（配体）1；MSI：微卫星不稳定；dMMR：DNA 错配修复；SCNAs：体细胞拷贝数改变；TME：肿瘤微环境；MSK-IMPACT：纪念斯隆凯特琳癌症中心综合突变分析以确定靶向治疗；FDA：美国食品和药物管理局；WES：全外显子测序；SNP：单核苷酸多态性；FDR：假发现率；DCR：疾病控制率；DDR：DNA 损伤反应和修复；MDSCs：髓源性抑制细胞；FAO：脂肪酸氧化。
