Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses Predict Improved Survival in Patients With Glioblastoma Multiforme

Abstract

Purpose: We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM). Patients and Methods: Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics. Results: Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a ‘partial’ combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p < .0001) as well as T-cell responses to the survivin97–111 peptide (p = .0152) correlated with longer survival among patients with GBM. Multivariate analysis identified survivin97–111-directed IFN-γ production with IL-2/IL-15/IL-21 conditioning (p = .024), and the combined presence of serum IFN-γ/TNF-α/IL-17a (p = .003) as independent predictors of survival. Conclusion: Serum cytokine patterns and lymphocyte reactivity to survivin97–111, particularly with IL-2, IL-15 and IL-21 conditioning may be instrumental in predicting survival among patients with GBM. This has implications for clinical follow-up of patients with GBM and the targeted development of immunotherapy for patients with CNS tumours. Keywords: Glioblastoma multiforme, Cytokine networks, Survivin, Immune response, Survival benefit, Immunotherapy