Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression

Abstract

IntroductionThe tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression.MethodsUsing in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME. Results and discussionNeutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1β, and IL-10 are associated with poor outcomes in patients with GB. ConclusionThese results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.

Cytokine Profile in Development of Glioblastoma in Relation to Healthy Individuals

“…Several SASP components, including IL-1β, IL-6, IL-8, and TNFα, are all potential targets for pharmacological inhibition; some of them already exist in the clinical practice and may be exploited to mitigate the deleterious effects of SASP in the relevant clinical context [22]. Interestingly, these cytokines are the key inflammatory mediators that trigger the inflammatory cycle in GBM and also promote carcinogenesis by avoiding growth suppression and apoptosis, inducing angiogenesis and metastasis, and maintaining cancer cell stemness [2,[23][24][25]. The concentration of cytokines in GBM cyst fluid highly correlates with white blood cell counts, suggesting an important interaction between tumor cells and the peripheral inflammatory status [24].…”

Prognostic and clinical pathological significance of the systemic immune-inflammation index in urothelial carcinoma: a systematic review and meta-analysis

“…Second, neutrophils can also affect tumor immune escape and drug resistance by regulating the expression of cytokines and chemical factors in the tumor microenvironment ( 57 ). In addition, some studies have found that the number and activity of central granulocytes are closely related to the prognosis of tumors, and the high density of central granulocyte infiltration is related to the malignant degree and poor prognosis of tumors ( 58 ). In contrast, lymphocytes are the primary immune cell type and play a crucial role in eliminating tumor cells through immune surveillance ( 59 , 60 ).…”

Nomograms based on the lymphocyte–albumin–neutrophil ratio (LANR) for predicting the prognosis of nasopharyngeal carcinoma patients after definitive radiotherapy

“…Neutrophils can inactivate T cells by secreting various cytokines, resulting in tumor immune evasion and progression 18 – 20 . Moreover, tumor-infiltrated neutrophils can promote tumor angiogenesis 21 , and tumor-neutrophil crosstalk sustains prolonged tumor activation 22 . Hence, various blood-based immunity-related biomarkers, including the neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have been reported to be independent prognostic factors in cancer patients 23 – 25 .…”