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

Introduction: The 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. Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME. Results and discussion: Neutrophils 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-1ß, and IL-10 are associated with poor outcomes in patients with GB. Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process.

Small extracellular vesicle-mediated bidirectional crosstalk between neutrophils and tumor cells.

Neutrophils are the first line of defense against tissue injury and play an important role in tumor progression. Tumor-associated neutrophils (TANs) mediate pro-tumor immunosuppressive activity and their infiltration into tumors is associated with poor outcome in a variety of malignant diseases. The tumor cell-neutrophil crosstalk is mediated by small extracellular vesicles (sEVs) also referred to as exosomes which represent a major mechanism for intercellular communication. This review will address the role of neutrophil-derived sEVs (NEX) in reprogramming the TME and on mechanisms that regulate the dual potential of NEX to promote tumor progression on one hand and suppress tumor growth on the other. Emerging data suggest that both, NEX and tumor-derived sEVs (TEX) carry complex molecular cargos which upon delivery to recipient cells in the tumor microenvironment (TME) modulate their behavior and reprogram them to mediate pro-inflammatory or immunosuppressive responses. Although it remains unknown how the balance between the often conflicting signaling of TEX and NEX is regulated, this review is an attempt to provide insights into mechanisms that underpin this complex bidirectional crosstalk. A better understanding of the signals NEX process or deliver in the TME might lead to the development of novel approaches to the control of tumor progression in the future.

Neutrophils: fast and furious-the nucleotide pathway.

Nucleotide signaling is a key element of the neutrophil activation pathway. Neutrophil recruitment and migration to injured tissues is guided by purinergic receptor sensitization, mostly induced by extracellular adenosine triphosphate (ATP) and its hydrolysis product, adenosine (ADO), which is primarily produced by the CD39-CD73 axis located at the neutrophil cell surface. In inflammation unrelated to cancer, neutrophil activation via purinergic signaling aims to eliminate antigens and promote an immune response with minimal damage to healthy tissues; however, an antagonistic response may be expected in tumors. Indeed, alterations in purinergic signaling favor the accumulation of extracellular ATP and ADO in the microenvironment of solid tumors, which promote tumor progression by inducing cell proliferation, angiogenesis, and escape from immune surveillance. Since neutrophils and their N1/N2 polarization spectrum are being considered new components of cancer-related inflammation, the participation of purinergic signaling in pro-tumor activities of neutrophils should also be considered. However, there is a lack of studies investigating purinergic signaling in human neutrophil polarization and in tumor-associated neutrophils. In this review, we discussed the human neutrophil response elicited by nucleotides in inflammation and extrapolated its behavior in the context of cancer. Understanding these mechanisms in cancerous conditions may help to identify new biological targets and therapeutic strategies, particularly regarding tumors that are refractory to traditional chemo- and immunotherapy.