Human virome profiling identified CMV as the major viral driver of a high accumulation of senescent CD8⁺ T cells in patients with advanced NSCLC

Circulating senescent CD8⁺ T (T₈sen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non–small cell lung cancer (aNSCLC). We aimed to better characterize T₈sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T₈sen cells were characterized by a higher expression of SA-βgal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with T₈sen. CMV was necessary but not sufficient to explain high accumulation of T₈sen (T₈sen^high status). In CMV⁺ patients, the proportion of T₈sen cells increased with cancer progression. Last, CMV-induced T₈sen^high phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti–PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of T₈sen-driven resistance to anti–PD-(L)1 antibodies in patients with aNSCLC.