The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications

Abstract

Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.

Keywords: Clinical applications; Functions; Heterogeneity; Neutrophils; Orchestrations; Origins; Subsets; TANs (tumor-associated neutrophils).

Fig. 1

The evolution of neutrophils in humans. In humans, neutrophils originate from GMPs residing within the bone marrow, which are characterized by the expression of CD34, CD38, and CD45RA [29, 30]. Subsequently, these GMPs differentiate into pro-neutrophils (pro-neutrophil 1 and pro-neutrophil 2) and pre-neutrophils, expressing biomarkers such as CD11b, CD66b, and CD15 [31, 32]. This specific stage of neutrophil development, characterized by the presence of immature neutrophils exhibiting relatively high levels of biomarkers such as CD11b, CD16b, CD71, and CD117, has been duly acknowledged [26, 31, 33]. Ultimately, neutrophils that express chemokine receptors (CXCR)4 and CXCR2 undergo final maturation and are subsequently released into circulation. The C-X-C Motif Chemokine Ligand (CXCL)12 expressed by bone marrow stromal cells activates the neutrophil receptor CXCR4 to retain it within the bone marrow. While under the stimulation of G-CSF, endothelial cells in the bone marrow upregulate CXCL2 expression to activate CXCR2 signaling, thereby facilitating the releasing of neutrophils from the bone marrow into circulation [34, 35, 36]. Conversely, under pathological circumstances, the presence of mature neutrophils exhibiting abnormal biomarkers or immature neutrophils within the peripheral blood of humans has been reported [37, 35, 38]

Fig. 2

Direct interaction between TANs and tumor cells. Interactions between tumor cells and TANs typically lead to two outcomes: promotion or suppression, with the former involving necrosis or growth. The former one can be induced by type I IFN, IFN-γ and TNF-α, while the latter one by TGF-β [41, 85]. Necrosis of tumor cells can be induced not only by Antibody-dependent cell-mediated cytotoxicity (ADCC) of TANs through the combination of Fc receptors (FcR) and monoclonal antibodies (mAbs), but also by DNA damage and mutations triggered by ROS and reactive nitrogen species (RNS) [82, 83, 88]. The latter pathway may exhibit a paradoxical effect of promoting tumor growth and migration [82, 83]. Moreover, TANs secrete various molecules that can stimulate tumor growth, such as neutrophil elastase (NE), prostaglandin E2 (PGE2), TGF-β, and TGF-α [–81]. Notably, mesenchymal cells expressing CD140a also produce PGE2, which contributes to the accumulation of lipid-rich TANs and subsequently fuels tumor growth through lipid oxidation [89]

Fig. 3

The multiple tumor-related inflammation pathways of TANs driving angiogenesis. TANs not only promote angiogenesis through angiopoietin, but also up-regulate the expression of Bv8, IL-8, and S100A8/A9 [104, 106, 107]. The secretion of MMP9 by TANs, in conjunction with a high NGAL expression in tumor cells, can confer a protective effect and promote angiogenesis via extracellular matrix (ECM) degeneration [98, 99]

Fig. 4

TANs’ role in tumor immunology. A specific subset of N1 neutrophils, characterized by the expression of HLA-DR and CD86, can be induced by GM-CSF and IFN-γ [109]. These neutrophils are capable of activating antitumor adaptive immunity by interacting with CD8⁺ T cells and CD4⁺ T cells through MHC-TCR binding [109]. Conversely, the presence of GM-CSF and IL-6 induces another subset of TANs that express CCL4 and CCL3, facilitating the recruitment of macrophages and thereby promoting tumor metastasis [112]. Additionally, TANs exhibiting elevated levels of CD54 and CD11b, along with reduced CD62L expression, have been shown to secrete CXCL10, IL23a, and Arg1. These molecules, in conjunction with IL-12 secreted by macrophages, collaborate to stimulate the secretion of IFN-γ by unconventional αβ T cells, thereby eliciting a type I immune response against tumor cells [116]. Another subset of TANs expressing CD274 (PD-L1), which is differentiated by lactate, can interact with T cells and subsequently hinder their cytotoxicity against tumors [112, 131]. Furthermore, B cells exhibiting high levels of CD45 and B220, as well as low level of CD138, have been reported to be recruited by TANs to plasma cells exhibiting low levels of B220 and CD138, as well as high level of CD45, by contrast [123]. These TANs secrete the cytokine BAFF (BLyS) and the proliferation-inducing ligand APRIL, which not only contribute to B cells recruitment but also the IgM production, along with its switching to IgG or IgA [124]. Noticeably, apart from molecules such as cytokine BAFF (BLyS), APRIL, and IL-21, TNF-α is also reported to increase the movement and support the migration of B cells along with CXCL12 or CXCL13 [123, 132]. Besides, researchers have pointed out the important function of NETs as well as the direct contact of BAFF and BAFF-R in the B cells recruiting process [124]

Fig. 5

The function of NETs in the TME. Tumor cells possess the ability to secrete various molecules, including G-CSF and NAMPT. G-CSF can induce the formation of NETs, which exhibit diverse biomedical behaviors such as epithelial-to-mesenchymal transition, capture of CTCs, and increased vascular permeability that contribute to tumor prognosis [133]. However, they can also exhibit laminin remodeling and immunosuppressive behaviors that promote tumor metastasis [133]. On the other hand, NAMPT can stimulate the formation of aged neutrophil-derived NETs with high CXCR4 expression and low CD62L expression, consequently promoting tumor metastasis [137]

Fig. 6

Neutrophil clearance. In cancer, the clearance of neutrophils is also mediated by key signaling molecules. This process exhibits distinct characteristics in both the tissue and circulation [36]. Aged neutrophils, which have a shorter lifespan, express increasingly high levels of CD16, CXCR4, CD10, and CD11b. They can either be recruited back into the bone marrow through a CXCR4/CXCL12-dependent pathway or be eliminated by macrophages in peripheral tissues [–144]