| Summary: | Despite the adoption of novel therapeutical approaches, the outcomes for glioblastoma (GBM) patients remain poor. In the present study, we investigated the prognostic impact of several clinico-pathological and molecular features as well as the role of the cellular immune response in a series of 59 GBM. CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were digitally assessed on tissue microarray cores and their prognostic role was investigated. Moreover, the impact of other clinico-pathological features was evaluated. The number of CD4+ and CD8+ is higher in GBM tissue compared to normal brain tissue (<i>p</i> < 0.0001 and <i>p</i> = 0.0005 respectively). A positive correlation between CD4+ and CD8+ in GBM is present (<i>r<sub>s</sub> =</i> 0.417—<i>p</i> = 0.001). CD4+ TILs are inversely related to overall survival (OS) (HR = 1.79, 95% CI 1.1–3.1, <i>p =</i> 0.035). The presence of low CD4+ TILs combined with low CD8+ TILs is an independent predictor of longer OS (HR 0.38, 95% CI 0.18–0.79, <i>p =</i> 0.014). Female sex is independently related to longer OS (HR 0.42, 95% CI 0.22–0.77, <i>p =</i> 0.006). Adjuvant treatment, methylguanine methyltransferase (<i>MGMT</i>) promoter methylation, and age remain important prognostic factors but are influenced by other features. Adaptive cell-mediated immunity can affect the outcomes of GBM patients. Further studies are needed to elucidate the commitment of the CD4+ cells and the effects of different TILs subpopulations in GBM.
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