| Title: | CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade |
| Journal: | Nature Medicine |
| Published: | 23 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40269332/ |
| DOI: | https://doi.org/10.1038/s41591-025-03647-1 |
| URL: | https://www.nature.com/articles/s41591-025-03647-1.pdf |
Publication 15803
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
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.</p>
14 Keywords
- Adult
- Aged
- CD8-Positive T-Lymphocytes
- CTLA-4 Antigen
- Cytomegalovirus
- Cytomegalovirus Infections
- Female
- Humans
- Immune Checkpoint Inhibitors
- Male
- Melanoma
- Middle Aged
- Programmed Cell Death 1 Receptor
- T-Box Domain Proteins
32 Authors
- Gusztav Milotay
- Martin Little
- Robert A. Watson
- Dylan Muldoon
- Sophie MacKay
- Ayako Kurioka
- Orion Tong
- Chelsea A. Taylor
- Isar Nassiri
- Louisa M. Webb
- Oluwafemi Akin-Adigun
- Julia Bremke
- Weiyu Ye
- Bo Sun
- Piyush Kumar Sharma
- Ros Cooper
- Sara Danielli
- Flavia Matos Santo
- Alba Verge de Los Aires
- Guangyi Niu
- Lea Cohen
- Esther Ng
- James J. Gilchrist
- Amanda Y. Chong
- Alex Mentzer
- Victoria Woodcock
- Nicholas Coupe
- Miranda J. Payne
- Michael Youdell
- Mark R. Middleton
- Paul Klenerman
- Benjamin P. Fairfax
Enabling scientific discoveries that improve human health