Molecular and immune landscape of tumours in geriatric patients with non-small cell lung cancer, melanoma and renal cell carcinoma.

Objective: 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. Methods and analysis: 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. Results: 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. Conclusion: Our findings reveal tumour type-specific expression profiles, TIMEs and response signatures to ICIs in patients ≥80, supporting further biomarker investigations in this population.