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