Naqash Abdul Rafeh, Floudas Charalampos S, Aber Etan, Maoz Asaf, Nassar Amin H, Adib Elio, Choucair Khalil, Xiu Joanne, Baca Yasmine, Ricciuti Biagio, Alessi Joao V, Awad Mark M, Kim Chul, Judd Julia, Raez Luis E, Lopes Gilberto, Nieva Jorge J, Borghaei Hossein, Takebe Naoko, Ma Patrick C, Halmos Balazs, Kwiatkowski David J, Liu Stephen V, Mamdani Hirva
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Center for Immuno-Oncology, National Cancer Institute, NIH, Bethesda, MD.
JCO Precis Oncol. 2024 Feb;8:e2300371. doi: 10.1200/PO.23.00371.
Non-small-cell lung cancer (NSCLC) with has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring comutations could have favorable outcomes to ICIs.
NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for versus NSCLC.
Overall, 12.6% of NSCLC tumors had a with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in NSCLC ( < .01). Compared with , tumors with had higher CD8+T cells and natural killer cells ( < .01), higher TMB ( < .001) and neoantigen load ( < .001), and increased expression of and ( < .01), along with higher expression ( < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with . In the DFCI cohort, compared with the cohort, the tumors had higher objective response rates (42.9% 16.7%; = .04) and also had longer TTF (14.5 4.5 months, adj = .054) with ICI.
NSCLC with comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.
伴有特定共突变的非小细胞肺癌（NSCLC）对免疫检查点抑制剂（ICI）的疗效较差。我们利用多组学技术评估了具有独特炎症性肿瘤免疫微环境（TIME）且伴有共突变的NSCLC亚型对ICI是否可能有良好疗效。
通过二代测序（DNA-Seq/592个基因）分析NSCLC肿瘤（N = 16,896）。一个亚组（n = 5,034）进行了基因表达谱分析（RNA-Seq/全转录组）。NSCLC的外显子水平新抗原负荷来自已发表的全免疫分析。使用微环境细胞群体（MCP）计数器从转录组谱中获取肿瘤免疫细胞含量。来自POPLAR/OAK（n = 34）和Rizvi等人的研究（n = 49）的ICI数据用于建立无进展生存期（PFS）模型，来自丹娜法伯癌症研究所（DFCI）的一个单独的ICI治疗队列（n = 53）用于评估特定共突变NSCLC与非特定共突变NSCLC的治疗失败时间（TTF）和肿瘤RECIST反应。
总体而言，12.6%的NSCLC肿瘤存在特定共突变，其中肿瘤突变负荷（TMB）高（≥10个突变/Mb）、PD-L1≥50%和微卫星高度不稳定的比例分别为38.3%、11.8%和0.72%。对干扰素-γ（STING）通路基因的特定共突变（n = 463）进行无监督层次聚类，确定了一个STING高聚类，其在特定共突变NSCLC中显著富集（P <.01）。与非特定共突变肿瘤相比，特定共突变肿瘤具有更高的CD8 + T细胞和自然杀伤细胞（P <.01）、更高的TMB（P <.001）和新抗原负荷（P <.001），以及 和 的表达增加（P <.01），同时糖酵解/谷氨酰胺代谢基因的表达也更高（P <.01）。对OAK/POPLAR和Rizvi等人的研究数据进行荟萃分析显示，特定共突变患者的PFS有改善趋势。在DFCI队列中，与非特定共突变队列相比，特定共突变肿瘤具有更高的客观缓解率（42.9%对16.7%；P =.04），并且接受ICI治疗时也有更长的TTF（14.5对4.5个月，P校正 =.054）。
伴有特定共突变的NSCLC是一个具有免疫活性TIME和代谢重编程的独特亚组。应利用这些特性来指导基于新型ICI的联合治疗方法的患者选择。
