The findings of the study showed that there are immune system cells that, despite the fact that their primary function is to attack and kill the cancer cells, actually act as “double agents” that increase and intensify the aggressiveness and threat of the tumor.
The study was led by Dr. Dinorah Friedmann-Morvinski of the George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, and her Ph.D. student and Prerna Magod Also participating in the study were Dr. Liat Rousso-Noori and Ignacio Mastandrea, also from the Faculty of Life Sciences, as well as other researchers from the Sackler Faculty of Medicine at Tel Aviv University and the Weizmann Institute of Science. The study was published in Cell Reports.
The researchers explain that usually, the scientific monitoring of the development of the cancerous tumor in animal models is carried out without an active immune system, in order to enable the absorption and growth of cancer cells in the body.
The disadvantage of this commonly-used model lies in the fact that the immune system either does not exist or does not function properly, which prevents researchers from monitoring the interaction between it and the tumor cells.
This allowed the cancer to grow gradually, to the point of the development of a massive tumor, which enabled the close monitoring of its development, and throughout the process, of the interaction between the cancer cells and different immune system cells.
In the study, the researchers found that cells called neutrophils play a critical role in interacting with the cancerous growth. Neutrophils are immune system cells that originate in the bone marrow, and whose purpose is to “swallow” or kill bacteria and fungi and fight the infections caused by them. “Neutrophils are the front-line soldiers of the immune system,” says Dr. Friedmann-Morvinski.
“When a tumor begins to develop, the neutrophils are among the first to mobilize and attack it in order to eliminate it.”
The researchers also found that the neutrophils remain in close proximity to the tumor throughout its development, and are continuously and consistently recruited from the bone marrow. The surprising thing that was discovered during this study is that the neutrophils “change sides:” Whereas at first, with the onset of the initial tumor, the neutrophils fight it, over time the neutrophils recruited to the cancerous area begin to support its development.
Dr. Friedmann-Morvinski says that “we learned that the neutrophils actually change their role. They are mobilized by the tumor itself, and from being anti-cancerous, become pro-cancerous; as a result, they aggravate the damage that the tumor itself creates.”
Moreover, the researchers found that the process by which the neutrophils change their properties can take place remotely, even before they progress towards the tumor itself.
“The study showed that the change in the properties of neutrophils takes place in the bone marrow itself—where there is no tumor at all: the cancerous tumor is located only in the brain, and from there it succeeds in changing the properties of the cells it recruits,” adds Dr. Friedmann-Morvinski.
“The new findings of this study may also shed light on immunotherapeutic therapies, which have been gaining a lot of momentum in recent years. In one type of immunotherapy treatment, T cells are removed from the patient’s body, processed, and returned to the body with increased healing abilities.
One of the major problems today is that even these cells that have been sent to heal are suppressed and their actions stifled. If we know how to change the interaction between neutrophils and T cells so that they are not suppressed, this will have implications for the effectiveness of immunotherapy.”
The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated with proteases and various inflammatory mediators.
Although NETs play a crucial role in defense against systemic infections, they also participate in non-infectious conditions, such as inflammation, autoimmune disorders, and cancer. Cancer cells recruit neutrophils (tumor-associated neutrophils, TANs), releasing NETs to the tumor microenvironment. NETs were found in various samples of human and animal tumors, such as pancreatic, breast, liver, and gastric cancers and around metastatic tumors.
The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between the immune system and cancer cells. According to the accumulated evidence, NETs awake dormant cancer cells, causing tumor relapse, as well as its unconstrained growth and spread. NETs play a key regulatory role in the tumor microenvironment, such as the development of distant metastases through the secretion of proteases, i.e., matrix metalloproteinases and proinflammatory cytokines.
NETs, furthermore, directly exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. The collected evidence also states that through the induction of the high-mobility group box 1, NETs induce the epithelial to mesenchymal transition in tumor cells and, thereby, potentiate their invasiveness. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation.
Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. NETs directly trigger tumor cell proliferation through their proteases or activating signals. This review focused on the pro-tumorigenic action of NETs, in spite of its potential to also exhibit an antitumor effect. NET components, such as myeloperoxidase or histones, have been shown to directly kill cancer cells.
A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread. This review sought to provide the most recent knowledge on the crosstalk between NETs and cancer, and bring more profound ideas for future scientists exploring this field.
Tumor-Infiltrating Neutrophils
The tumor microenvironment (TME) comprises different non-malignant cell types and an extracellular matrix (ECM), altogether named the stroma. The stroma consists of the basement membrane, immune cells, cancer-associated fibroblasts (CAFs), pericytes, and vascular endothelial cells [10]. Tumor cell proliferation, the evasion of immune surveillance, and the spread and metastasis are affected by the changes in the composition, function, and communication between all stromal components [10,11].
Amongst various immune cells within the TME, such as dendritic cells, lymphocytes, macrophages, granulocytes, and fibroblasts, infiltrating neutrophils, in concert with other cell types, play a prominent role in cancer development [11]. However, the pro-tumor functions of tumor-infiltrating neutrophils have only recently come to the light. Consistently, various mediators produced by tumor or stromal cells stimulate granulopoiesis, neutrophil release from the bone marrow, and the migration of these cells [11]. These mediators include growth factors: G-CSF, GM-CSF and CXC chemokines, and CCL3 [11].
Recently, different studies started to highlight that cancer cells release chemokines attracting neutrophils to tumor microenvironments [12,13]. In the recent past, tumor-associated neutrophils (TANs) have emerged as important contributors to the tumor biology. However, consistent and continuous evidence has confirmed that these cells appear to play an important role in the entire process of cancerogenesis, followed by the metastatic spread to distant organs [12].
TANs are capable of polarization into two populations (N1 and N2) according to cytokine production patterns and effector functions. These two populations present either an anti-tumorigenic “N1” phenotype or, fed by TGFβ, a pro-tumorigenic “N2” phenotype [12].
Both N1 and N2 cells bear similar surface markers to peripheral blood neutrophils, i.e., CD66b+, CD11b+, CD15+, CD16+, HLA-DR−, and arginase-1+ [13]. In fact, due to the often-shared cell morphology and the overlap of the expression of these surface markers between the different functional groups, it is difficult to clearly distinguish between the subtypes N1 and N2 [13].
N1 neutrophils can effectively eliminate tumor cells via lysis, indirect cytotoxicity or the induction of tumor cell apoptosis. N1 cells exhibit increased cytotoxicity and a reduced immunosuppressive ability due to the increased release of TNFα, Fas, ICAM-1, and ROS, and through a decreased arginase expression [14].
On the other hand, N2 cells promote immunosuppression, support tumor growth, invasion, epithelial–mesenchymal transition (EMT), angiogenesis and the metastasis of cancer cells [15]. N2 neutrophils express high levels of arginase, MMP-9 VEGF, and numerous chemokines (for example CXCL4, CCL2, and CCL5). The affluence of these cells corresponds with poor clinical outcomes [15].
The tumor-secreted TGF-β was shown to transform N1 TANs (tumor-suppressive phenotype) into N2 TANs (tumor-promoting phenotype) [15]. Infiltrating neutrophils continue to promote tumor development by secreting pro-inflammatory and pro-angiogenic chemokines and cytokines, such as matrix metallopeptidase 9 (MMP9) and interleukin 6 (IL-6) [14,15].
Circulating tumor cells shed from the primary tumor sites are disseminated via blood or lymphatic vessels and reach distant organs. In a recent study, neutrophils emerged as important players supporting circulating tumor cells survival during hematogenous dissemination [16].
Furthermore, it was confirmed that neutrophils escort circulating tumor cells, increasing the dynamics of cell cycle progression [16]. Wculek et al. have identified neutrophils as the main drivers in establishing the pre-metastatic microenvironment in different murine breast cancer models [17].
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431228/
More information: Prerna Magod et al, Exploring the longitudinal glioma microenvironment landscape uncovers reprogrammed pro-tumorigenic neutrophils in the bone marrow, Cell Reports (2021). DOI: 10.1016/j.celrep.2021.109480
