Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery

Abstract

Patients with glioblastoma multiforme (GBM) are immunosuppressed and have a broad range of immunological defects in both innate and adaptive immune responses. GBMs are frequently infected with human cytomegalovirus (HCMV), a virus capable of causing immunosuppression. In 42 HCMV-positive GBM patients in a clinical trial (VIGAS), we investigated T-cell phenotypes in the blood and assessed their relation to survival. Blood was collected before and 3, 12, and 24 weeks after surgery, and the frequency of T-cell subsets was compared with that in 26 age-matched healthy controls. GBM patients had lower levels of CD3 cells than the controls, but had significantly higher levels of CD4⁺CD28^- T cells before and 3 and 12 weeks after surgery and increased levels of CD4⁺CD57⁺ and CD4⁺CD57⁺CD28⁺ T cells at all-time points. These T-cell subsets were associated with both immunosenescence and HCMV infection. GBM patients also had higher levels of γδ T cells at all-times after surgery and lower levels of CD4⁺CD25⁺ cells before and 3 weeks after surgery than healthy controls. Overall survival was significantly shorter in patients with higher levels of CD4⁺CD28^- T cells (<i>p =</i> 0.025), CD4⁺CD57⁺ T (<i>p =</i> 0.025) cells, and CD4⁺CD28^-CD57⁺CD28^- T cells (<i>p <</i> 0.0004) at 3 weeks after surgery. Our findings indicate that signs of immunosenescence in the CD4⁺ compartment are associated with poor prognosis in patients with HCMV-positive GBMs and may reflect the HCMV activity in their tumors.