Abstract
In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.
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Background
Neutrophils have been recognized as the most abundant innate immune cells in both bone marrow and peripheral blood [1]. They are rapidly recruited into sterile or infected inflammation sites and show high plasticity and a strong effector response. Perhaps to avoid unnecessary tissue damage, neutrophils possess a short lifespan [2]. Therefore, the abundance of neutrophils relies on constant replenishment via granulopoiesis in the bone marrow. Their origin is hematopoietic stem cells, which give rise to lymphoid-primed multipotent progenitors (LMPPs). Neutrophils are derived from the early committed neutrophil progenitor (proNeu1), a subtype of granulocyte–monocyte myeloid progenitor (GMP) that develops from LMPPs [3, 33].
Neutrophils promote angiogenesis and immunosuppression
Coussens et al. documented that MMP-9 supplied by bone marrow-derived neutrophils and other hematopoietic cells contributes to squamous carcinogenesis [34]. MMP-9 produced by neutrophils also contributes to the carcinogenesis of pancreatic islet carcinoma and lung cancer accelerating angiogenesis [35]. NETs promote inflammation in subjects with nonalcoholic steatohepatitis, resulting in the development of hepatocellular carcinoma, which is inhibited by deoxyribonuclease treatment or peptidyl arginine deaminase type IV knockout, decreasing NET formation [36]. Furthermore, NETs positively correlate with the increased number of regulatory T cells (Tregs) in cancer by facilitating naïve CD4+ T cell metabolic reprogramming. Therapies targeting the interaction between these two cell types or inhibiting Treg activity may promote cancer immunosurveillance and prevent hepatocellular carcinoma formation [45]. The structure of NETs formed by granule proteins and DNA induces the proliferation of cancer cells through high mobility group protein B1 (HMGB1) and NE [46,47,48]. In hematological malignancies, levels of NETs are found to positively correlated with lymphoma progression or childhood acute leukemia development [121, 122]. The interaction between neutrophils and CTCs promotes cell cycle progression in the blood and expands the metastatic potential of CTCs [123]. According to a recent study, ROS produced by neutrophils increase NETs, especially in obese cancer-bearing mice, which weakens endothelial junctions and promotes the extravasation of cancer cells[124]. In addition, several studies have shown that direct interaction between neutrophils and cancer cells activates neutrophils, increases the migration of cancer cells, promotes the anchoring of cancer cells to endothelial cells, and ultimately helps cancer cells exit blood vessels [123, 125].
Neutrophils facilitate cancer cell extravasation
Finally, metastatic cancer cells in distant tissues typically remain dormant for an extended period, during which infiltrating neutrophils release MMP-9 to promote angiogenesis, triggering the growth of dormant metastases. In addition, continued inflammation induces the formation of NETs, which are needed to wake dormant cancer cells. A mechanistic analysis has shown that two NEs and MMP-9, which are associated with NETs, cleave laminin. Cleaved laminin induces the proliferation of dormant cancer cells by activating α3β1-integrin signaling [72].
A related interesting phenomenon has been observed. Before disseminated cancer cells arrive, neutrophils accumulate in distant organs, forming the premetastatic niche. Neutrophils have been observed to aggregate in the lungs prior to the occurrence of metastasis in mouse models of MMTV-PyMT mammary cancer, breast cancer with nicotine exposure and melanoma, all of which are closely associated with the occurrence of pulmonary metastasis [179], a fungal-derived prototype agonist of trained immunity, trained neutrophils in mice to enhance the anticancer activity of neutrophils. These results, in turn, prove that neutrophils are highly plastic (Fig. 1C).
Interaction between neutrophils and other microenvironmental cells
Cancer is highly heterogeneous and is considered one of its hallmarks. The tumor contains cancer cells and noncancerous cells such as neutrophils, macrophages, T cells, adipocytes, stromal cells and others constituting the microenvironment. All these cells communicate directly or indirectly. Thus, neutrophils in cancer not only have a relationship with the T cells mentioned above but also affect or are affected by other cells. During advanced colorectal cancer progression, cancer stem cell-derived exosomes containing triphosphate RNAs prime neutrophils for cancer development and depletion of neutrophils with antibodies attenuate the tumorigenicity of these cancer stem cells [180]. In obese patients with pancreatic cancer, crosstalk among pancreatic stellate cells, neutrophils and adipocytes mediated by IL1β promotes PDAC. Genetic or pharmacological targeting of this circuit provides a potential method for pancreatic cancer treatment [181]. Cancer-associated fibroblasts are considered one of the important stromal cells contributing to cancer development. A recent report identified that one of the underlying mechanisms as NET induction. This induction is driven by increased amyloid and β-secretase expression in fibroblasts [182].
Discussion and perspectives
We speculate that the cancer microenvironment may reprogram neutrophils to achieve conversion between anticancer polarity and cancer-promoting one. First, as previously described, neutrophils are heterogeneous in patients with cancer, which may result from the reprogramming of mature neutrophils. Many data indicate that neutrophil precursors support cancer growth and metastatic progression. Second, cancer cells functionally shape the cancer microenvironment by secreting various cytokines, chemokines and other factors, which provides the necessary environmental conditions for the reprogramming of surrounding neutrophils. Neutrophils acquiring new transcriptional activity, which could be characterized as diverse neutrophil subsets, based on single cell RNA sequencing analysis under specific microenvironment support the hypothesis [183]. Our previous review also stated that cancer cells undergo cellular reprogramming either spontaneously or after anticancer treatment [184]. All of these findings suggest the possibility of reprogramming both cancer cells and neutrophils in the cancer microenvironment. Third, our experiments show that mature neutrophils are reprogrammed into multipotent progenitors in the presence of a chemical cocktail [185]. In other words, neutrophils have the potential to undergo cell reprogramming.
More evidence of neutrophil reprogramming is illustrated below. Neutrophils transdifferentiate into other cell types. One study has shown that human postmitotic neutrophils are reprogrammed into macrophages via growth factors. The molecular mechanisms underlying functional changes in neutrophils has been discovered that GM-CSF controls the overexpression of FATP2 in neutrophils through the activation of the STAT5 transcription factor, thereby enabling neutrophils to obtain immunosuppressive activity and promote cancer progression in mice [143]. In addition, metabolic reprogramming of neutrophils leads to functional changes, as a metabolic shift of innate immune cells, including neutrophils, is observed in pulmonary diseases, accompanied by an impaired normal immune function of these cells.
In conclusion, neutrophils exert both pro-cancer and anticancer effects on the initiation, growth and metastasis of cancer, and these different functions are accompanied by the existence of different neutrophil subpopulations. Because neutrophils normally possess antimicrobial and anticancer functions, functional transformation or abnormal cell differentiation must occur. Here, we propose a hypothesis that the cancer microenvironment or clinical treatment may induce the reprogramming of neutrophils. In clinical practice, an elevated NLR serves as a prognostic indicator and the inhibition or reversal of neutrophil reprogramming can also be employed as a potential therapeutic strategy, e.g., conversion of neutrophils into antigen-presenting cells by FcγR engagement can exhibit immunotherapeutic effect on cancer [186].
Conclusions
Neutrophils would be a promising cell target population for anticancer therapy, although their roles in cancer are dual and remain to be further investigated. Direct target neutrophils or indirect target microenvironment factors reprogramming neutrophil plasticity might be potential therapeutic strategies.
Availability of data and materials
Not applicable.
Abbreviations
- ADCC:
-
Antibody-dependent cellular cytotoxicity
- COVID-19:
-
Coronavirus disease 2019
- CTCs:
-
Circulating cancer cells
- FATP2:
-
Fatty acid transport protein 2
- GEMMs:
-
Genetically engineered mouse models
- G-MDSCs:
-
Granulocytic myeloid-derived suppressor cells
- GMP:
-
Granulocyte–monocyte myeloid progenitor
- HGF:
-
Hepatocyte growth factor
- HMGB1:
-
High mobility group protein B1
- HOCl:
-
Hypochlorous acid
- HPRT:
-
Hypoxanthine phosphoribosyl transferase
- IFNγ:
-
Interferon-γ
- IL-1RA:
-
IL-1 receptor antagonist
- iNOS:
-
Inducible nitric oxide synthase
- LMPPs:
-
Lymphoid-primed multipotent progenitors
- MPO:
-
Myeloperoxidase
- NE:
-
Neutrophil elastase
- NETs:
-
Neutrophil extracellular traps
- NK:
-
Natural killer
- NLR:
-
Neutrophil-to-lymphocyte ratio
- NOS:
-
Nitric oxide synthase
- PDAC:
-
Pancreatic ductal adenocarcinoma
- proNeu1:
-
Early committed neutrophil progenitor
- proNeu2:
-
Intermediate progeny
- preNeu:
-
Preneutrophil
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- TANs:
-
Tumor-associated neutrophils
- TGFβ:
-
Transforming growth factor-β
- TNF:
-
Tumor necrosis factor
- VEGF:
-
Vascular endothelial growth factor
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This work is supported by the National Natural Science Foundation of China (92068101, 31871498), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (828313), the Project from National Research Center for Translational Medicine at Shanghai (TMSK-2021–106), the Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research (2019CXJQ01), and Samuel Waxman Cancer Research Foundation.
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**ong, S., Dong, L. & Cheng, L. Neutrophils in cancer carcinogenesis and metastasis. J Hematol Oncol 14, 173 (2021). https://doi.org/10.1186/s13045-021-01187-y
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DOI: https://doi.org/10.1186/s13045-021-01187-y