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

Abstract

PurposeWe 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 MethodsPeripheral 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.ResultsApproximately 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.ConclusionSerum 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.

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

“…Previous studies investigating effect of either plasma or serum IL-6 levels on glioma survival mostly involve small cohorts and use a range of cut-offs, sampling times, and methods of detection (Supplementary File 1). Despite these limitations, eight out of 10 studies (12,(23)(24)(25)(26)(27)(28)(29)(44)(45)(46) with reported survival outcome do not find association of high plasma IL-6 with short survival (Supplementary File 1), supporting our results. A study on cytokine networks including IL-6 in GBM, found a trend toward survival benefit using a combined IL-4/IL-5/IL-6 serum profile, but no benefit with a partial combination (24), suggesting that combined immune-profiles may be related to GBM propagation and survival.…”

“…IL-6 and YKL-40 regulate each other's transcription levels along with a range of other mediators (9,18) and IL-6 infusion increased YKL-40 secretion in plasma in healthy volunteers (19). High or increasing levels of circulating IL-6 or YKL-40 have been associated with decreased survival of patients with glioma either alone or in combination with other biomarkers (12,(20)(21)(22)(23)(24), although not consistently (25)(26)(27)(28)(29)(30) (Supplementary File 1).…”

Survivin at a glance

“…Conversely, a third strategy aimed at generating survivin vaccines for cancer immunotherapy has successfully passed proof-of concept and has already produced encouraging results in the clinic (Kaneko et al, 2014). Specifically, several survivin-directed immunisation platforms have been developed that are well-tolerated in patients and give rise to robust immunological responses with initial evidence of clinical activity as both monotherapy or in combination in hard-totreat malignancies; these are SurVaxM for malignant glioblastoma multiformis (Fenstermaker and Ciesielski, 2014) and the multiepitope vaccine EMD640744 in solid tumours (Lennerz et al, 2014;Zhenjiang et al, 2018).…”

Relationship between circulating inflammatory factors and glioma risk and prognosis: A meta‐analysis

“…On the other hand, only eight studies concentrating on the prognostic significance of circulating inflammatory factors in glioma patients were included. The prognostic values of IL‐6 and CRP in glioma were examined in five and four studies, respectively. The characteristics and quality evaluation of these prognostic‐related studies are presented in Table .…”

“…Some research has suggested that CRP and IL‐6 could effectively predict clinical outcomes in patients with glioma . In contrast, other studies showed no association between these factors and the prognosis of patients with glioma . To elucidate the essential relationship between circulating inflammatory factors and the risk of glioma as well as their prognostic values in glioma in clinical practice, we performed this meta‐analysis.…”