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Neuroblastoma is a common childhood tumor that mainly affects young children, especially toddlers, and, with a survival rate in high-risk patients of less than 50%. Treatment for high-risk neuroblastoma involves a combination of induction chemotherapy, most commonly doxorubicin, surgical tumor resection, stem cell transplantation, radiotherapy, and immunotherapy.
Cytokine | Immunologic Function | Interaction with Immune Checkpoint Inhibitor (ICI) |
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TNFα | A proinflammatory cytokine primarily produced by activated macrophages, T lymphocytes, and NK cells. TNF plays major roles in bone remodeling, infection control, and leukocyte trafficking [13]. | TNF has been shown to induce resistance to immunotherapies and acts as a negative biomarker for prognosis. TNFα increases the expression of PD-L1 in tumor cells. Studies have also shown that a TNF-β blockade combined with ICI, such as anti-PD1, has a better therapeutic effect than ICI therapy alone [13]. |
IFNγ | A proinflammatory cytokine primarily produced by NK cells, activated T lymphocytes, B-cells, and antigen presenting (AP) cells. IFNγ has many immunomodulatory roles including antiviral and antitumor functioning [13]. | IFNγ has an antitumor mechanism targeted by ICIs. It increases tumor immunogenicity, suppresses cancer cell proliferation, increases NK cell cytotoxic functioning, and recruit’s tumor-reactive T cells [13]. Clinic studies have reported increased IFNγ levels following anti-PD-1 ICI therapy and improved prognosis. Further, IFNγ has been shown to be a positive biomarker for successful ICI therapy [13]. |
IL-6 | IL-6 has pro and anti-inflammatory properties. Its function is involved in cell survival and growth, immune system regulation, and carcinogenesis. Importantly, it has been shown to promote tumor transmission [21]. | IL-6 has been shown to have a negative role in immunotherapy. It has been reported that increased levels of IL-6 induce the production of myeloid-derived suppressor cells (MDSCs), which promote an immunosuppressive TME. Studies have shown that combining anti-IL6 with ICI treatment, such as anti-PD-1 immunotherapy, fosters increased anti-tumor activity and improved prognosis [21]. |
IL-8 | A proinflammatory cytokine produced by macrophages. Its primary roles are to activate neutrophils stimulated by cellular stresses and stimulate endothelial cell proliferation. IL-8 levels have been shown to reflect tumor burden [21]. | The interaction between IL-8 and ICI therapy is unclear. However, studies have reported that increased levels of IL-8 are correlated with longer overall survival (OS) in non-small-cell lung cancer (NSCLC) patients treated with nivolumab, and anti-PD-1 ICI [21]. |
TGF-β | A proinflammatory cytokine produced by leukocytes and stromal cells. It serves many functions, including driving the differentiation of T helper 17 (Th17) cells and regulating cell growth, proliferation, and apoptosis [4][22]. | TGF-β inhibits early cancer cells by inducing cell-cycle arrest and apoptosis. However, TGF-β has been shown to have cancer-promoting properties in later stages. Mouse models used to study urothelial cancer have demonstrated that combining anti-PD-1 therapy with the TGF-β antibody reduced the TGF-β pathway and induced tumor infiltration by cytotoxic T cells, resulting in tumor suppression. Similarly, another study has shown that combing ICI therapy with the TGF-β antibody resulted in improved prognosis compared with monotherapy [13]. |
IL-17 | IL-17 has pro- and anti-inflammatory properties. It induces neutrophil-mediated inflammation while also suppressing autoimmune diseases [23][24]. Importantly, studies investigating colorectal cancer have shown that IL-17 exhibits protumoral properties, especially during the early stages [24]. | IL-17 signaling has been shown to promote carcinogenesis. Further, studies have shown that inhibiting signaling from this cytokine slows down oncogenesis initiation, suggesting that IL-17 inhibition may be used to halt the early stages of tumor growth. Importantly, studies utilizing mouse models have found that increased IL-17 levels were correlated with high PD-L1 expression. Further, combining IL-17 and a PD-1 blockade induced higher levels of cytotoxic T cells and tumor regression [25]. |
Il-21 | IL-21 has pro- and anti-inflammatory properties. It regulates various immune cells such as NK and cytotoxic T cells while hindering the pro-inflammatory mechanisms of macrophages. IL-21 also exhibits anti-tumor properties [26]. | Studies have found that IL-21 hinders tumor development, especially during early stages [27]. Additionally, more recent studies using mouse models have demonstrated that combining an immune checkpoint blockade, such as anti PD-L1, with IL-21 administration increased antitumor activity, characterized by increased CD8+ T cell proliferation and by increased infiltration by, and memory of, effector T cells [27]. |
Cytokine | Function | Role in Neuroblastoma |
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VEGF | VEGF acts as a pro-inflammatory cytokine by increasing endothelial cell permeability, by inducing the expression of endothelial cell adhesion molecules, and via its ability to act as a monocyte chemo-attractant [50]. | Studies looking at the expression of several markers in NB xenografts have shown that some angiogenic factors including VEGF-A, -B and -C are associated with advanced NB stage [51]. |
CCL2 | Chemokine CCL2 (also known as monocyte chemo-attractant protein-1, MCP-1) is one of the vital chemokines that control the migration and infiltration of monocytes/macrophages [52]. | The infiltration of neuroblastoma cells by invariant NKT (iNKT) cells was found to correlate with the expression of the chemokine CCL2 by the tumor [53]. |
CXCL12 | CXCL12 acts through its receptors CXCR4 and CXCR7. CXCR4 stimulation leads to the activation of numerous signaling pathways depending on the associated cell types, while CXCR7 has mainly been shown to be involved in scavenging CXCL12, although it can activate a MAP kinase pathway through β-arrestin in several systems [54]. | CXCL12 and CXCR4 have been demonstrated to be overexpressed in NB cell lines in addition to primary metastatic NB. This hints at the role of CXCL12 in its connection to autocrine/paracrine signaling of tumor growth instead of the development of metastatic pathways [55]. |
CXC3CL1 | CXC3CL1 is an unusual chemokine expressed on the cell surface and acting as adhesion molecule by binding to its receptor CX3CR1.7 and is also expressed in a variety of human tissues and cell lines, where it mediates leukocyte migration and adhesion [56]. | It has been shown in animal models that CX3CL1 is able to inhibit NB growth and eradicate metastasis when used in combination with IL-12 through the attraction of immune cells to the tumor site [57]. |
IL-6 | IL-6 and VEGF are the best characterized cytokines to stimulate tumor growth and metastasis, while others, such as IFN-γ, can exert anti-NB activity by inducing tumor cell apoptosis and inhibiting angiogenesis [58]. | IL-6 is introduced into the bone marrow by the bone marrow stromal cells (BMSC) which promotes the growth and survival of neuroblastoma cells [59]. |
IL-7 | IL-7 is a cytokine that stimulates proliferation of all cells in the lymphoid lineage (B, T and NK cells) [60]. | A study using a humanized mouse model of metastatic NB showed that the combinatory therapy of human γδ T cells, hu14.18 anti-GD2 antibody, and Fc-IL-7 was able to increase the survival rate of the subject animals [61]. |
IL-10 | IL-10 is an immunosuppressive cytokine consistently expressed in the tumor microenvironment. Studies carried out in different tumor models have demonstrated that blocking the IL-10R relieves immunosuppression in the tumor microenvironment and reinstates immune response directed at malignant cells [62]. | This response was observed in an NB model wherein an antibody targeting the IL-10 receptor was used in combination with liposomal oligonucleotides to enhance the immune response. The observed immune response was larger compared with the use of oligonucleotides alone [63]. |
IFN-β | Interferon-beta reduces myeloid dendritic concentrations in peripheral blood. It also alters the function of dendritic cells and other APCs to downregulate antigen presentation and the ability of APCs to stimulate T cell responses [64]. | IFN-β was found to increase the sensitivity of NB cells to the cytotoxic effects of the chemotherapy drug temozolomide (TMZ) through the mitigation of DNA repair enzyme (MGMT) expression [65]. |