Role of tumour- associated neutrophils in tissue material and systemic neutrophil inflammation in colorectal cancer patients

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide. Immune response is appear to be inseparable component of each part of tumorigenesis. Moreover, several studies have shown that some populations of neutrophils, called tumor-associated neutrophils (TANs) can be also actively involved in the tumor growth, anggenesis and development of the distant metastases in various cancer tissues.

The Role of Neutrophils in the Pathogenesis of Chronic Lymphocytic Leukemia

Tumor-associated neutrophils appear to be a crucial element of the tumor microenvironment that actively participates in the development and progression of cancerous diseases. The increased lifespan, plasticity in changing of phenotype, and functions of neutrophils influence the course of the disease and may significantly affect survival. In patients with chronic lymphocytic leukemia (CLL), disturbances in neutrophils functions impede the effective immune defense against pathogens. Therefore, understanding the mechanism underlying such a phenomenon in CLL seems to be of great importance. Here we discuss the recent reports analyzing the phenotype and functions of neutrophils in CLL, the most common leukemia in adults. We summarize the data concerning both the phenotype and the mechanisms by which neutrophils directly support the proliferation and survival of malignant B cells.

Role of Tumor-Associated Neutrophils in the Molecular Carcinogenesis of the Lung

Tumorigenesis is largely influenced by accompanying inflammation. Myeloid cells account for a significant proportion of pro-inflammatory cells within the tumor microenvironment. All steps of tumor formation and progression, such as the suppression of adaptive immune response, angio- and lymphangiogenesis, and the remodeling of the tumor stroma, are to some degree influenced by tumor-associated immune cells. Tumor-associated neutrophils (TANs), together with tumor-associated macrophages and myeloid-derived suppressor cells, count among tumor-associated myeloid cells. Still, the exact molecular mechanisms underlying the tumorigenic effects of TANs have not been investigated in detail. With this review of the literature, we aim to give an overview of the current data on TANs, with a special focus on lung cancer.

Neoadjuvant/Perioperative Treatment Affects Spatial Distribution and Densities of Tumor Associated Neutrophils and CD8+ Lymphocytes in Gastric Cancer

Tumor associated neutrophils (TANs) and cytotoxic T cells (CTLs) are part of the tumor microenvironment of gastric cancer (GC). We explored their tumor biological significance in neoadjuvantly/perioperatively treated GC. Immunostaining was performed on whole tissue sections of 173 GCs, using antibodies directed against myeloperoxidase (MPO) and CD8. Stained specimens were digitalized, and the densities of TANs and CTLs were assessed separately in the mucosa, tumor surface, tumor center, invasion front, and tumor scar. The densities were correlated with clinicopathological patient characteristics. Compared with a historical cohort of 449 treatment naive GCs, the TAN density in the invasion front was significantly lower in neoadjuvantly/perioperatively treated GCs. TAN density in the tumor center and invasion front correlated with tumor regression. TAN density also correlated with CTL density in the tumor center and invasion front. A high density of CTL in the tumor center correlated with an improved overall survival and tumor specific survival. We show that neoadjuvant/perioperative (radio-) chemotherapy impacts on the immune microenvironment of GC, while also depending on sex. The density of TANs in neoadjuvantly/perioperatively treated GCs differed from findings made in a treatment naive GC cohort.

TAMI-38. TUMOR-ASSOCIATED NEUTROPHILS IN GLIOBLASTOMA PROMOTE THE PERIVASCULAR GLIOMA STEM-LIKE CELL NICHE VIA OSTEOPONTIN SECRETION

Among clinical analyses, elevated neutrophil-lymphocyte ratio has been correlated with poor outcomes of glioblastoma patients independent of other prognostic factors. Additionally, our flow cytometric studies of primary patient samples found neutrophil percentage to be significantly higher in higher-grade glioma versus lower-grade glioma. Tumor-associated neutrophils (TANs) comprise less than 2% of the glioblastoma microenvironment. While TANs were initially considered passive bystanders due to their short-lived nature, investigation of TANs in other cancers revealed distinct pro-tumoral roles. Therefore, we transcriptomically characterized glioblastoma TANs and defined their oncologic effects. Transcriptomic analysis of patient-matched TANs versus peripheral blood neutrophils revealed that functionally quiescent circulating neutrophils infiltrate IDH1-wild type glioblastoma via leukotriene B4 chemoattraction, where tumor cells morphologically and transcriptomically activate them to become TANs. Single-cell RNA-sequencing of patient-matched TANs and peripheral blood neutrophils revealed a subset of tumor-activated neutrophils which adopt a pro-tumoral secretory phenotype, marked by activation of the IL-17 signaling pathway and high osteopontin production. Using immunofluorescence stains of primary patient glioblastoma sections, we demonstrated that activated, myeloperoxidase-positive TANs reside in the perivascular niche of glioblastoma in close proximity to glioblastoma stem-like cells (GSCs) and CD31-positive endothelial cells. Further analysis in culture demonstrated that TAN-secreted osteopontin drives the formation, self-renewal, and proliferation of GSC-containing neurospheres. These results were validated using a syngeneic stem cell-derived IDH1-wild type murine glioblastoma model in vivo. Thus, while TANs are rare in glioblastoma, their enrichment in the glioblastoma perivascular niche uniquely positions them to support the GSCs that are crucial to therapeutic resistance of GBM.

Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation. A Review of the Molecular Mechanisms

Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE2. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.