The Recruitment of Neutrophils to the Tumor Microenvironment Is Regulated by Multiple Mediators

Abstract

Neutrophils sense and migrate towards chemotactic factors released at sites of infection/inflammation and contain the affected area using a variety of effector mechanisms. Aside from these established immune defense functions, neutrophils are emerging as one of the key tumor-infiltrating immune cells that influence cancer progression and metastasis. Neutrophil recruitment to the tumor microenvironment (TME) is mediated by multiple mediators including cytokines, chemokines, lipids, and growth factors that are secreted from cancer cells and cancer-associated stromal cells. However, the molecular mechanisms that underlie the expression and secretion of the different mediators from cancer cells and how neutrophils integrate these signals to reach and invade tumors remain unclear. Here, we discuss the possible role of the epithelial to mesenchymal transition (EMT) program, which is a well-established promoter of malignant potential in cancer, in regulating the expression and secretion of these key mediators. We also summarize and review our current understanding of the machineries that potentially control the secretion of the mediators from cancer cells, including the exocytic trafficking pathways, secretory autophagy, and extracellular vesicle-mediated secretion. We further reflect on possible mechanisms by which different mediators collaborate by integrating their signaling network, and particularly focus on TGF-β, a cytokine that is highly expressed in invasive tumors, and CXCR2 ligands, which are crucial neutrophil recruiting chemokines. Finally, we highlight gaps in the field and the need to expand current knowledge of the secretory machineries and cross-talks among mediators to develop novel neutrophil targeting strategies as effective therapeutic options in the treatment of cancer.

Genomic analysis of paired IDHwt glioblastomas reveals recurrent alterations of MPDZ at relapse after radiotherapy and chemotherapy

“…They did not observe a decreasing neutrophil recrutment at relapse. In our study, we observed that three neutrophil chemotactic factor genes were more frequently lost at relapse but neutrophil recrutment is certainly lead by complementary pathways [24]. Finally, the EORTC study sequenced 287 genes and observed that mutation status changed in approximatively 20% of events with changes observed for all examined genes.…”

Promising prognostic value of Transglutaminase type 2 and its correlation with tumor-infiltrating immune cells in skin cutaneous melanoma

“… Immune cell type Gene markers Spearman’s correlation p -value Ref. General T-cell activation CD3D 0.521 1.34e-26 [ 55 ] CD3E 0.539 8.58e-29 [ 56 ] CD4 + T cells (Th1 and Th2) TBX21 0.509 2.44e-25 [ 57 ] HLA-DMB 0.595 3.77e-36 [ 46 ] HLA-DRA 0.567 2.58e-32 [ 47 ] TGF- β 0.499 3.32e-24 [ 48 ] CRTAM 0.524 5.46e-27 IL12A 0.237 5.083e-6 IL12B 0.381 5.11e-14 Dendritic cells (DCs) VEGFC 0.517 3.36e-25 [ 58 ] CCL4 0.536 2.15e-28 [ 36 ] CCL5 0.536 2.08e-28 CD40L 0.455 6.18e-20 [ 59 ] CD40 0.585 1.15e-34 Neutrophils (N1 population) CXCL5 0.329 1.26e-10 [ 60 ] CSF2 0.391 9.82e-15 [ 61 ] <...…”

Neutrophil metabolism in the cancer context

“…Comparably to inflamed tissues during infection, tumors secrete factors into the circulation that can enhance granulopoiesis and augment infiltration of neutrophils into the TME [31,32]. Here, G-CSF secretion favors hematopoietic cell differentiation toward the neutrophil lineage and enhances the exit of neutrophils into the circulation [33].…”