The prognostic significance of tumor-associated neutrophils and circulating neutrophils in glioblastoma (WHO CNS5 classification)

Abstract

Background Tumor-associated neutrophils (TANs) in the tumor microenvironment are prognostic biomarkers in many malignancies. However, it is unclear whether TANs can serve as a prognostic marker for clinical outcomes in patients with glioblastoma (GBM), as classified according to World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (CNS5). In the present study, we analyzed correlations of TANs and peripheral blood neutrophils prior to radiotherapy with overall survival (OS) in GBM (CNS5). Methods RNA-seq expression profiles of patients with newly diagnosed GBM (CNS5) were extracted from The Cancer Genome Atlas (TCGA), and The Chinese Glioma Genome Atlas (CGGA). TAN infiltration was inferred using CIBERSORTx algorithm. Neutrophil counts prior to radiotherapy in newly diagnosed GBM (CNS5) were obtained from the First Affiliated Hospital of Fujian Medical University. The prognostic value of TANs and peripheral blood neutrophils before radiotherapy was investigated using Kaplan-Meier analysis and Cox proportional hazards models. The robustness of these findings was evaluated by sensitivity analysis, and E values were calculated. Results A total of 146 and 173 individuals with GBM (CNS5) were identified from the TCGA and CGGA cohorts, respectively. High infiltration of TANs was of prognostic of poor OS in TCGA (HR = 1.621, 95% CI: 1.004–2.619) and CGGA (HR = 1.546, 95% CI: 1.029–2.323). Levels of peripheral blood neutrophils before radiotherapy (HR = 2.073, 95% CI: 1.077–3.990) were independently associated with poor prognosis. Sensitivity analysis determined that the E-value of high TANs infiltration was 2.140 and 2.465 in the TCGA and CGGA cohorts. Conclusions TANs and peripheral blood neutrophil levels before radiotherapy are prognostic of poor outcomes in GBM (CNS5).

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma

“…The "call" of neutrophils to circulate in the blood in patients with glioblastoma who are receiving radiotherapy may be greater with larger fraction sizes, as seen in hypofractionated radiotherapy. Like myeloid cells, a large number of circulating tumor-associated neutrophils is a poor prognostic indicator, suggesting maybe the resulting inflammation from a hypofractionated course of radiotherapy delivered to the brain should not be sustained if optimal immunity is desired (26). Both neutrophils and monocytes have been reported to demonstrate radiotherapy resistance, potentially contributing to tumor immune system evasion (27).…”

Evaluating hematologic parameters in newly diagnosed and recurrent glioblastoma: Prognostic utility and clinical trial implications of myelosuppression

“… 8 In addition to lymphopenia, there has been some evidence of the possible prognostic significance of neutropenia in GBM. 9 , 10 Lastly, a high ratio between the neutrophil and lymphocyte (NLR) has been shown to be associated with a more pro-inflammatory state and worse outcomes, 11 though its prognostic significance relative to lymphopenia is unclear. Better understanding of these changes to commonly measured blood counts may be important for optimizing management of GBM patients.…”