Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer

Wallen ZD, Ko H, Nesline MK, Hastings SB, Strickland KC, Previs RA, Zhang S, Pabla S, Conroy J, Jackson JB, Saini KS, Jensen TJ, Eisenberg M, Caveney B, Sathyan P, Severson EA, Ramkissoon SH. Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer. Front Immunol. 2024 Jun 21;15:1413956. doi: 10.3389/fimmu.2024.1413956. PMID: 38975340; PMCID: PMC11224431. ABSTRACT Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC. DATA AVAILABILITY: De-identified, individual-level patient data, genomic variants, and individual immune gene expression data used in the manuscript can be found in this repository (https://zenodo.org/record/11396552). An R markdown file with R code used to perform the analyses and generate figures is also provided in the repository along with the data. All versions of software used are provided in the Methods section of the manuscript. Raw sequencing data were derived from routine clinical testing of real-world patients and cannot be shared publicly. Data for immune gene expression signatures are not publicly available due to a non‑provisional patent filing covering the methods used to generate and analyze these data but are available from the corresponding author on reasonable request.Wallen ZD、Ko H、Nesline MK、Hastings SB、Strickland KC、Previs RA、Zhang S、Pabla S、Conroy J、Jackson JB、Saini KS、Jensen TJ、Eisenberg M、Caveney B、Sathyan P、Severson EA、Ramkissoon SH. 真实世界综合基因组与免疫 profiling（comprehensive genomic and immune profiling, CGIP）揭示非小细胞肺癌（non-small cell lung cancer, NSCLC）患者肿瘤存在显著的年龄与性别相关基因组及免疫特征差异。《Frontiers in Immunology》（Front Immunol），2024年6月21日；15：1413956. DOI：10.3389/fimmu.2024.1413956. PMID：38975340；PMCID：PMC11224431. 摘要 非小细胞肺癌（non-small cell lung cancer, NSCLC）年轻患者（<50岁）是一类具有独特临床病理特征的重要患者群体，相较于老年患者，其可靶向基因组变异更为富集。然而，既往针对年轻NSCLC患者的研究结论存在不一致，且鲜有研究将性别纳入分析范畴，同时缺乏针对肿瘤免疫微环境年龄相关差异的相关研究。本研究对8230例NSCLC患者进行回顾性分析，对比年轻与老年患者的基因组变异及免疫原性标志物，并同时考量男女患者间的差异。本研究将老年患者定义为≥65岁人群，并以<45岁至<65岁的5年滑动阈值划分不同的年轻患者亚组。此外，在另一独立NSCLC患者队列中，本研究利用上述观察结果，探究年龄与性别联合效应对接受免疫治疗联合或不联合化疗的患者生存结局的影响。研究发现，相较于老年患者的肿瘤，年轻患者的肿瘤具有独特的基因组及免疫微环境特征。年轻患者的肿瘤富集临床相关基因组变异，且基因表达模式提示免疫系统激活程度降低，这一现象在男性患者中尤为显著。进一步分析显示，仅接受免疫治疗的年轻男性患者，其生存结局显著差于≥65岁的男性患者，而联合化疗可缩小这一生存差异。与之相反，仅接受免疫治疗时，年轻女性患者与≥65岁女性患者的生存结局无显著差异；但当接受免疫治疗联合化疗时，年轻女性患者的生存结局显著优于≥65岁女性患者。本研究结果表明，综合基因组与免疫 profiling（CGIP）可为年轻NSCLC患者的临床治疗提供指导依据，并支持为晚期年轻NSCLC患者提供更广泛的CGIP覆盖范围。 数据可用性： 本论文中使用的去标识化个体水平患者数据、基因组变异数据及个体免疫基因表达数据，可在本仓库（https://zenodo.org/record/11396552）获取。本仓库同时提供了用于开展分析及生成图表的R Markdown文件及配套R代码。本研究使用的所有软件版本均已在论文的方法部分列明。原始测序数据来源于真实世界患者的常规临床检测，无法公开共享。由于针对本研究中用于生成及分析这些数据的方法已提交非临时专利申请，因此免疫基因表达特征相关数据无法公开获取，但可在合理请求后从通讯作者处获得。