Choucair Khalil, Elliott Andrew, Oberley Matthew James, Walker Phillip, Salama April K, Saeed Azhar, Mamdani Hirva, Uprety Dipesh, El-Deiry Wafik S, Beltran Himisha, Liu Stephen V, Kim Chul, Naqash Abdul Rafeh, Lou Emil, Chen Lujia, Saeed Anwaar
Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA.
Caris Life Sciences, Phoenix, Arizona, USA.
BMJ Oncol. 2025 Jan 16;4(1):e000551. doi: 10.1136/bmjonc-2024-000551. eCollection 2025.
Cancer patients aged ≥80 years present unique characteristics affecting response to immune checkpoint inhibitors (ICIs), with unidentified molecular differences. This study aimed to explore potential biomarkers of response to ICI in patients ≥80 years.
We analysed tumour samples (n=24 123) from patients ≥80 (versus<80) with non-small cell lung cancer (NSCLC), melanoma (MEL), and renal cell cancer (RCC). Using gene expression deconvolution, we investigated differences in tumour microenvironment (TIME) composition. Then, using next-generation sequencing and programmed death-ligand 1 (PD-L1) assessment, we evaluated gene expression differences between age groups and across tumour types, with a focus on ageing-related processes such as DNA damage response (DDR), immune checkpoint (IC) and metabolism-related genes. In a subset of patients ≥80 (n=1013), gene clustering and differential gene expression analyses were carried out to identify potential tumour-type specific expression patterns in responders to ICI.
Significant differences in TIME composition were seen in patients with NSCLC and MEL. In patients ≥80, tumour mutational burden was lower in patients with NSCLC, higher in MEL and RCC had fewer PD-L1+tumours. DDR, IC and metabolism-related gene enrichments were distinct in patients ≥80. In patients ≥80 treated with ICIs (n=1013), there were no significant differences in survival between gene clusters, but differential gene expression analysis identified potential tumour-type specific expression patterns in responders.
Our findings reveal tumour type-specific expression profiles, TIMEs and response signatures to ICIs in patients ≥80, supporting further biomarker investigations in this population.
80岁及以上癌症患者具有影响免疫检查点抑制剂（ICI）反应的独特特征，其分子差异尚不明确。本研究旨在探索80岁及以上患者对ICI反应的潜在生物标志物。
我们分析了年龄≥80岁（与<80岁相比）的非小细胞肺癌（NSCLC）、黑色素瘤（MEL）和肾细胞癌（RCC）患者的肿瘤样本（n = 24123）。使用基因表达反卷积，我们研究了肿瘤微环境（TIME）组成的差异。然后，使用下一代测序和程序性死亡配体1（PD-L1）评估，我们评估了年龄组之间以及不同肿瘤类型之间的基因表达差异，重点关注与衰老相关的过程，如DNA损伤反应（DDR）、免疫检查点（IC）和代谢相关基因。在年龄≥80岁的患者亚组（n = 1013）中，进行基因聚类和差异基因表达分析，以识别ICI反应者中潜在的肿瘤类型特异性表达模式。
在NSCLC和MEL患者中观察到TIME组成存在显著差异。在≥80岁的患者中，NSCLC患者的肿瘤突变负担较低，MEL患者的肿瘤突变负担较高，而RCC患者中PD-L1 +肿瘤较少。≥80岁的患者中，DDR、IC和代谢相关基因富集情况不同。在接受ICI治疗的≥80岁患者（n = 1013）中，基因簇之间的生存率无显著差异，但差异基因表达分析确定了反应者中潜在的肿瘤类型特异性表达模式。
我们的研究结果揭示了80岁及以上患者中肿瘤类型特异性表达谱、TIME和对ICI的反应特征，支持对该人群进行进一步的生物标志物研究。
