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

Abstract

$These authors share senior authorship.Keywords: cytomegalovirus, glioblastoma, immunosenescence, survival, T cells Abbreviations: GBM, glioblastoma multiforme; HCMV, human cytomegalovirus; PBMC, peripheral blood mononuclear cell; Valcyte, valganciclovir; WBC, white blood cell countPatients 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 C CD28 ¡ T cells before and 3 and 12 weeks after surgery and increased levels of CD4 C CD57 C and CD4 C CD57 C CD28 C 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 gd T cells at all-times after surgery and lower levels of CD4 C CD25 C cells before and 3 weeks after surgery than healthy controls. Overall survival was significantly shorter in patients with higher levels of CD4 C CD28 ¡ T cells (p D 0.025), CD4 C CD57 C T (p D 0.025) cells, and CD4 C CD28 ¡ CD57 C CD28 ¡ T cells (p < 0.0004) at 3 weeks after surgery. Our findings indicate that signs of immunosenescence in the CD4 C compartment are associated with poor prognosis in patients with HCMV-positive GBMs and may reflect the HCMV activity in their tumors.

Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

“…Unexpectedly, the senescence marker KLRG1 was markedly reduced and only presented by a fraction of T cells in the tumor compartment, while CD57 showed an inverse expression pattern, with reduced prevalence in CD8 þ TILs. In one of the first studies providing evidence of alterations in T-cell activation in GBM, Fornara and colleagues (43), demonstrated that a high prevalence of CD4 þ CD57 þ T cells in the blood of patients with GBM correlated with immunosenescence and decreased survival. Extending this work, we observed that CD57 was primarily expressed on CD4 þ TILs, while being reduced on CD8 þ T cells.…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…Furthermore, CMV‐specific CD57 + CD4 + T cells may also represent a mature cellular subset capable of up‐regulating surface CD107a expression (a degranulation marker), although their ability to lyse virus‐infected cells may be compromised due to reduced intracellular content of cytotoxic granules . These findings suggest that markers of immunosenescence in the CD4 + compartment are likely to be associated with poor survival in patients with CMV‐positive GBM and may reflect CMV activity in transformed tissue . However, other reports examining tumour‐infiltrating lymphocytes and in PBMC from patients with cancer show that ‘exhausted’ T cells, e.g.…”

“…These T cells were unable to produce multiple cytokines and displayed limited cytolytic function . Patients with GBM exhibited a lower frequency of CD3 + T cells compared to healthy individuals but had significantly higher numbers of CD4 + CD28 − T cells before, and after 3 and 12 weeks after surgery in addition to increased levels of CD4 + CD57 + and CD4 + CD57 + CD28 + T cells at all time‐points measured . These T‐cell subsets have been associated with both immunosenescence and CMV infection, as CD57 expression increases with age and in patients with cancer .…”

“…115 Patients with GBM exhibited a lower frequency of CD3 + T cells compared to healthy individuals but had significantly higher numbers of CD4 + CD28 À T cells before, and after 3 and 12 weeks after surgery in addition to increased levels of CD4 + CD57 + and CD4 + CD57 + CD28 + T cells at all time-points measured. 116 These T-cell subsets have been associated with both immunosenescence and CMV infection, as CD57 expression increases with age [117][118][119] and in patients with cancer. 120 Furthermore, CMV-specific CD57 + CD4 + T cells may also represent a mature cellular subset capable of up-regulating surface CD107a expression (a degranulation marker), although their ability to lyse virus-infected cells may be compromised due to reduced intracellular content of cytotoxic granules.…”

“…119 These findings suggest that markers of immunosenescence in the CD4 + compartment are likely to be associated with poor survival in patients with CMV-positive GBM and may reflect CMV activity in transformed tissue. 116 However, other reports examining tumour-infiltrating lymphocytes and in PBMC from patients with cancer show that 'exhausted' T cells, e.g. defined by PD-1 expression, may in fact represent antigen-specific T cells that had more recently encountered their nominal target antigen.…”