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<p>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<sup>+</sup> patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8<sup>+</sup> 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<sup>+</sup> T cells from CMV<sup>−</sup> patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV<sup>+</sup> hazard ratio for death: 1.02, <i>P</i> = 0.92), whereas CMV<sup>+</sup> single-agent anti-PD-1 ICB recipients had improved overall survival (CMV<sup>+</sup> hazard ratio for death: 0.37, <i>P</i> &lt; 0.01), a finding also seen in CMV<sup>+</sup> adjuvant single-agent anti-PD-1 ICB recipients (CMV<sup>+</sup> hazard ratio for recurrence: 0.19, <i>P</i> = 0.03). We identify <i>TBX21</i>, encoding T-bet, as a transcriptional driver of CMV-associated CD8<sup>+</sup> T cell gene expression, finding that <i>TBX21</i> expression is predictive of overall survival (hazard ratio: 0.62, <i>P</i> = 0.026). CMV<sup>+</sup> patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, <i>P</i> = 2.2 × 10<sup>−5</sup>), with lower incidence of colitis (<i>P</i> = 7.8 × 10<sup>−4</sup>) and pneumonitis (<i>P</i> = 0.028), an effect replicated in non-melanoma ICB recipients (<i>n</i> = 58, <i>P</i> = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, <i>P</i> = 1.8 × 10<sup>−4</sup>), indicating CMV seropositivity may protect against MM. Specifically, patients with <i>BRAF</i>-mutated MM are less likely to be CMV<sup>+</sup> (odds ratio = 2.2, <i>P</i> = 0.0054), while CMV<sup>−</sup> patients present 9 yr earlier with <i>BRAF</i> wild-type MM (<i>P</i> = 1.3 × 10<sup>−4</sup>). This work reveals an interaction between CMV infection, MM development according to <i>BRAF</i> 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>

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CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade

  • 期刊论文

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  • 发表日期：

    2025年4月23日

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  • 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

摘要

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.