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 (T 8 sen) 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 T 8 sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T 8 sen 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 T 8 sen. CMV was necessary but not sufficient to explain high accumulation of T 8 sen (T 8 sen high status). In CMV + patients, the proportion of T 8 sen cells increased with cancer progression. Last, CMV-induced T 8 sen 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 T 8 sen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.