Enhanced neutrophil activity is associated with shorter time to tumor progression in glioblastoma patients

Abstract

Glioblastoma multiforme (GBM) is a highly malignant tumor with a poor outcome that is often positive for human cytomegalovirus (HCMV). GBM patients often have excessive numbers of neutrophils and macrophages near and within the tumor. Here, we characterized the cytokine patterns in the blood of GBM patients with and without Valganciclovir treatment. Furthermore, we determined whether neutrophil activation is related to HCMV status and patient outcome. Blood samples for analyses of cytokines and growth factors were collected from 42 GBM patients at the time of diagnosis (n = 42) and at weeks 12 and 24 after surgery. Blood neutrophils of 28 GBM patients were examined for CD11b expression. The levels of pro- and anti-inflammatory cytokines and chemokines-including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IL-17A, transforming growth factor (TGF)-β1, interferon-γ, interferon-α, tumor necrosis factor α, and monocyte chemoattractant protein (MCP)-1were analyzed with a bead-based flow cytometry assay. During the first six months after surgery, neutrophil activity was increased in 12 patients and was unchanged or decreased in 16. Patients with increased neutrophil activity had enhanced IL-12p70, high grade HCMV and a shorter time to tumor progression (TTP) than patients without or decreased neutrophil activity (median TTP; 5.4 vs. 12 months, 95% confidence interval; 1.6-10 vs. 0.1-0.6, hazard ratio = 3 vs. 0.4, = 0.004). The levels of IL-12p70 were significantly decreased in Valganciclovir treated patients (n = 22, T 12W vs. T 24W, = 0.03). In conclusion, our findings suggest that neutrophil activation is an early sign of tumor progression in GBM patients.

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

“…Neutrophil activation is a poor prognostic clinical sign in GB. 30 Excess neutrophils have a pathophysiological trophic role of their own in driving GB growth, independent of any immunological role, 1,50-55 and as reviewed throughout this article.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[105][106][107][108][109][110] Accordingly, RCD can no longer be perceived as immunogenic when: (1) the intracellular stress responses regulating the emission of ICD-associated DAMPs are pharmacologically or genetically ablated in cancer cells; or (2) when the molecular machinery dedicated to DAMP detection is inhibited or ablated. 13,44,84,91,93,97 Moreover, ICD-driven immunity can no longer operate in the presence of general immunological defects, 111 such as (1) an intrinsically low antigenicity of cancer cells, owing to low levels of TAAs or downregulation of MHC Class I molecules [112][113][114][115][116][117][118][119] ; (2) an increased immunological tolerance of the host, secondary to increased amounts of immunosuppressive cytokines, [120][121][122][123][124][125][126][127][128] or inhibitors of chemotaxis, [129][130][131][132][133][134] increased tumor infiltration by immunosuppressive cell populations, [135][136][137][138][139][140]…”

Serological and viraemic status of human cytomegalovirus infection in patients with colorectal cancer is not correlated with viral replication and transcription in tumours

“…The other limitation is that almost all of the patients in the present study, either with or without HCMV present in their tumours, were seropositive for HCMV IgG, suggesting a nearly 100 % chronic, latent HCMV infection in these patients. In a recent study of glioma, *30 % of the patients were seronegative for HCMV, despite the detection of viral nucleic acids and proteins in tumour specimens (Rahbar et al, 2015). Further investigation is needed to clarify whether HCMV exists in tumours of HCMV-seronegative CRC patients.…”