Table 1.
Cytokines correlated to treatment response in solid tumors and HNSCC.
| Reference | Role/Action | Cytokine/Chemokine |
|---|---|---|
| [16,17] | TNF-β is secreted by T and B lymphocytes. It shares approximately 30% structural homology with TNF-α. It plays an important role in host defense against infection and the growth of some tumors. | TNF-β |
| [16] | As TNF-β, TNF-α exerts a wide variety of effects on diverse cell types through gene modulation of growth factors, cytokines, and transcription factors. In particular, like IL-1, TNF-α is a macrophage product and has the property to induce bone resorption, procoagulant activity, fibroblast growth, and expression of adhesion molecules on endothelial cells. TNF-α induces depletion of IFN-γ. Recently, TNF patterns were used to score HNSCC. High expression of TNF family members correlates with better responses. A favorable pattern is associated with p53 negative, not EGFR amplification, and HPV positive tumors. Additionally, TNF-α is correlated with CD4 and CD8 cell infiltrations. |
TNF-α |
| [18] | VEGF is the key mediator of angiogenesis in cancer, in which it is upregulated by oncogene expression, a variety of growth factors, and hypoxia. It induces epithelial to mesenchymal transition. | VEGF |
| [19] | IL-6 is produced by macrophages and monocytes, fibroblasts, activated T lymphocytes, and endothelial cells (in response to IL-1 and TNF-α. IL-6 causes hepatocytes to synthesize plasma acute phase proteins and is a growth factor for malignant plasma cells and hematopoietic stem cells. | IL-6 |
| [20,21] | IL-8 is secreted by monocytes, fibroblasts, epithelial cells, astrocytes, keratinocytes, synovial cells, and various tumor cells. It has chemotactic receptor agonist property and causes neutrophils’ shape changes, chemotaxis, and exocytosis. IL-8 increases angiogenesis and correlates with high macrophage infiltrates. | IL-8 |
| [22,23] | IL-10 is secreted by activated T cells. It can inhibit both T cells and NK cells and macrophage function (reducing the secretion of cytokines from Th1 T-cell clones and macrophage functions, including microbicidal properties). It stimulates B cells. | IL-10 |
| [24] | IL-21 is secreted by activated T cells and NK cells; it regulates a wide range of immune cells, including T and B cells, NK cells, DCs, and macrophages, as well as non-immune cells, including epithelial cells and keratinocytes. It activates the Janus kinase (JAK1/3)-signal transducer and activator of transcription (STAT) signaling pathway. | IL-21 |
| [25] | CCL-2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection. CCL-2 is implicated in the pathogenesis of several diseases characterized by monocytic infiltrates. It correlates to macrophage accumulation in cancer. | CCL-2 |
| [26,27] | TGF-β is able to induce both pro- and anti-tumoral effects. It affects proliferation and differentiation in a wide variety of cell types. It regulates extracellular matrix proteins and cell adhesion. It affects mesenchymal differentiation and is a potent chemotactic agent for various cell types, including monocytes and fibroblasts. It suppresses the activity of B and T lymphocytes, macrophages, and NK cells, regulating cytokine production by different cell types. | TGF-β |
| [28,29] | IL-2 is secreted by activated T cells, NK cells, and dendritic cells. It is known for its pleiotropic effect. It can promote T-cell and NK cell cytotoxicity activity and modulates T-cell differentiation programs in response to antigens. It has been used for the therapy of renal cell carcinoma and melanoma. In vitro IL-2 induces regression in a few HNSCC patients. | IL-2 |
| [30] | It is mainly secreted by activated T cells, NK cells, eosinophils, and basophils. Its activity is correlated to IL-13. It regulates antibody production, hematopoiesis, and inflammation and is also involved in developing effector T-cell responses. | IL-4 |
| [31] | IL-5 is produced mainly by lymphocytes, eosinophils monocytes, and macrophages. IL-5 stimulates antibody, eosinophil differentiation and proliferation and tumor cell migration and activation through STAT5 signaling. | IL-5 |
| [32] | IL-12 is a potent, pro-inflammatory cytokine. It has anti-tumor activity, and it counteracts IL-23 effect. It increases activation and cytotoxic capacities of T and NK cells and inhibits pro-tumoral macrophages and myeloid–derived suppressor cells. | IL-12 |
| [33] | IL-13 inhibits macrophage production of TNF, IL-1β, and pro-inflammatory chemokines, but can upregulate the synthesis of IL-12 by DCs and macrophages. IL-13 impairs antibody-dependent cytotoxicity. IL-13 stimulates B cell activation. IL-13 also promotes isotype switching to IgE and IgG1 and matrix expression (VCAM-1). | IL-13 |
| [34] | IL-15 is an inflammatory cytokine. It is secreted primarily by monocytes and macrophages. It stimulates TNF-α, IL-1β, inflammatory chemokines, T and B cells, and NK cells. It is regulated post-transcriptionally at the levels of translation and intracellular trafficking. | IL-15 |
| [35] | IL-1 stimulates CAFs, which produce CXCL1, CXCL8, and MMP-1. IL-1β increases neutrophils to the TME, and neutrophil accumulation has been related to poor outcomes in HNSCC. IL-12 stimulates VEGF and recruits T regulatory cells. | IL-1β |
CAF, Cancer-Associated Fibroblast; CCL—Chemotaxis towards CC chemokine Ligand; CXCL, chemokine (C-X-C) Ligand; DC, Dendritic Cell; HNSCC, Head and Neck Squamous Cell Carcinoma; HPV, Human Papilloma Virus; IFN, Interferon; IL, Interleukin; JAK-STAT, Janus Kinase-Signal Transducer and Activator of Transcription; MMP, Matrix Metalloproteinase; NK, Natural Killer; TGF, Tumor Growth Factor; TME, Tumor Microenvironment; TNF, Tumor Necrosis Factor; VCAM—Vascular Cell Adhesion Molecule; VEGF, Vascular Endothelial Growth Factor.