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Automated Cell Enrichment of Cytomegalovirus-specific T cells for Clinical Applications using the Cytokine-capture System
Published on: October 5, 2015
CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint
Gusztav Milotay1,2, Martin Little1,2,3,4, Robert A Watson1,2,3,4
1MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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.
Insights
Cytomegalovirus (CMV) infection impacts T cell immunity in melanoma patients receiving immune checkpoint blockade (ICB). CMV positivity is linked to better survival with single-agent anti-PD-1 ICB and fewer adverse events, suggesting a protective role.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Cytomegalovirus (CMV) is a common herpesvirus impacting T cell immunity.
- Immune checkpoint blockade (ICB) is a key therapy for metastatic melanoma (MM).
- The interplay between CMV infection, T cell responses, and ICB efficacy in melanoma is not fully understood.
Purpose of the Study:
- To investigate the oncological consequences of CMV infection in patients with metastatic melanoma receiving ICB.
- To explore the impact of CMV serostatus on T cell gene expression and response to different ICB strategies.
- To determine if CMV infection influences the incidence of immune-related adverse events (irAEs) during ICB therapy.
Main Methods:
- Analysis of prospectively recruited patients (n=341) with metastatic melanoma receiving ICB (anti-CTLA-4/anti-PD-1 or anti-PD-1 alone).
- Assessment of T cell counts, neutrophil-to-lymphocyte ratio, and CD8+ T cell gene expression (including TBX21).
- Comparison of overall survival, recurrence rates, and incidence of irAEs (colitis, pneumonitis) based on CMV serostatus and ICB regimen.
- Analysis of CMV seropositivity rates in melanoma patients versus controls and correlation with BRAF mutation status.
Main Results:
- CMV+ patients exhibited distinct immune profiles and improved overall survival with single-agent anti-PD-1 ICB.
- Combination anti-CTLA-4/anti-PD-1 ICB induced CMV-associated gene expression in CD8+ T cells from CMV- patients.
- TBX21 expression was identified as a driver of CMV-associated CD8+ T cell gene expression and predicted better survival.
- CMV+ patients had a significantly lower incidence of grade 3+ irAEs, including colitis and pneumonitis, across ICB therapies.
- CMV seropositivity was less frequent in MM patients, particularly those with BRAF-mutated melanoma, suggesting a protective effect against MM development.
Conclusions:
- CMV infection influences T cell responses and outcomes in melanoma patients undergoing ICB.
- Single-agent anti-PD-1 ICB efficacy is enhanced in CMV+ melanoma patients.
- CMV infection is associated with a reduced risk of severe immune-related adverse events during ICB.
- CMV serostatus and BRAF mutation status are important factors in melanoma development and response to immunotherapy.
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