CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade
Menée à l'aide de modèles murins, de données de la "UK Biobank" et d'échantillons sanguins prélevés sur 341 patients infectés par le cytomégalovirus (CMV) et atteints d'un mélanome traité par anti-PD1, cette étude met en évidence, par rapport aux patients non infectés par le CMV, une amélioration de la survie et une survenue plus tardive d'événements indésirables
Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV− patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10−5), with lower incidence of colitis (P = 7.8 × 10−4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10−4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV− patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10−4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.
Nature Medicine , article en libre accès 2025