Table 1.
Varied Roles of Cytokines in Anticancer Immunity
| Cytokine | Secreting Cell | Cancer Immunoregulation |
|---|---|---|
| IL-2 | CD4+ T cells, CD8+ T cells, NK cells, DCs, mast cells | ↑ CD4+ T cell differentiation; ↑ CD8+ T cell cytotoxicity; ↑ T cell proliferation; ↑ NK cell proliferation and activation.77,98 |
| IL-7 | Thymic stromal and mesenchymal cells, lymphatic endothelial cells, intestinal epithelial cells | ↑ T cell, B cell, and NK cell proliferation.99 |
| IL-15 | DCs, monocytes, epithelial cells | ↑ T cell and NK cell activation and proliferation.100,101 |
| IL-21 | CD4+ T cells, NKT cells | ↑ CD8+ T cell, NK cell, and NKT cell cytotoxicity.102,103 |
| IFN-α, IFN-β | Lymphocytes (NK cells, B cells, and T cells), macrophages, fibroblasts, endothelial cells, osteoblasts | ↑ DC maturation and activation; ↑ MHC class I expression on tumor cells; ↑ NK cell maturation and cytolytic effect.104,105 |
| IL-12 | DCs, phagocytes (monocytes/macrophages and neutrophils) | ↑ CTL and NK cell cytotoxicity; ↑ IFN-γ secretion by T cells, NK cells, ILCs; ↑ antigen presentation.18 |
| IFN-γ | CD4+ T cell, CD8+ T cells, NK cells, B cells, NKT cells, professional APCs |
Anticancer: ↑ Cell surface MHC class I expression; ↑ T cell, NK cell, and NKT cell migration into tumors; ↑ initial priming and differentiation of CTLs; ↓ tumor proliferation directly; ↓ tumor angiogenesis.23,106 Pro-cancer: ↓ Effector function of tumor-specific T cells or NK cells (upregulating expression of PD-L1 and PD-L2 in tumor cells and other stromal cells including immune infiltrating cells); ↑ CTLA-4 expression on tumor cells.107,108 |
| TNF-α | Macrophages and some other myeloid cells, malignant cells |
Anticancer: Recombinant TNF increases the permeability of tumor blood vessels, enhancing the effect of combined chemotherapy and destroying tumor vasculature.27 Pro-cancer: Endogenous TNF facilitates tumor angiogenesis, enhances malignant cell survival, and induces EMT and local immune suppression.27 |
| IL-1 (IL-1α, IL-1β) | Macrophages, monocytes, fibroblasts, DCs, B lymphocytes, NK cells, microglia, epithelial cells |
Anticancer: IL-1β induces Th1 and Th17 responses.109 Pro-cancer: ↑ Tumor angiogenesis; sustains immunosuppressive activity of MDSCs and TAMs.22 |
| IL-18 | Macrophages |
Anticancer: ↑ Activation of cytotoxic T cells and NK cells; ↑ perforin-mediated cytotoxicity in NK cells.19,110 Pro-cancer: ↑ Tumor angiogenesis and metastasis; ↑ tumor immune evasion.20,21,111 |
| GM-CSF G-CSF |
T cells, B cells, macrophages, mast cells, epithelial cells, fibroblasts macrophages, endothelial cells | ↑ DC and macrophage expansion and activation; ↑ ADCC through regulation of neutrophils, monocytes and macrophages.112 |
| EPO | Kidney cells | ↑ Expansion of erythroid progenitor and precursor cells.113 |
| Multi-CSF (IL-3) | T cells, basophils | ↑ Proliferation of hematopoietic stem cells; ↑ proliferation and differentiation of myeloid cells.114,115 |
| CCL21 | Stromal cells within T cell areas of lymph nodes, lymphatic endothelial cells, high endothelial venules, spleen, Peyer’s patches | ↑ T cell and DC infiltration in tumor.41,116 |
| TGF-β | Multiple leukocyte and stromal cell lineages | ↓ T cell proliferation; ↓ CD8+ T cell function; ↑ Treg generation; ↓ IFN-γ production by NK cells; ↓ MHC class II and costimulatory molecule expression on DCs.9,10 |
| VEGF | Macrophages, keratinocytes, tumor cells, platelets, mesangial cells in kidney | ↑ Tumor angiogenesis; ↓ DC maturation; ↑ immunosuppressive cells (eg, regulatory T cells, TAMs, MDSCs); ↓ T cell function.24–26 |
| FGF | Macrophages, mast cells, endothelial cells, fibroblasts, bone marrow mesenchymal stem cell | ↑ Immune evasion and angiogenesis in the tumor microenvironment; FGF2 alters macrophage polarization towards a pro-tumorigenic phenotype.117,118 |
| IGF | Cancer-associated fibroblasts, bone marrow stromal cells, intestinal epithelial cells, many immune cells | ↓ DC maturation and function.119,120 |
| EGF | TAMs, anterior pituitary cells, kidney cells, salivary gland cells | ↑ Macrophage-tumor cell interaction and tumor cell invasion; ↑ regulatory T cell-suppressive function.121,122 |
| IL-4 | Th2 cells, basophils, mast cells, NKT cells | ↓ CTL cytotoxicity; ↑ Th2 responses while inhibiting Th1 development; stabilizes Th2 status of CD4+ cells.15,16 |
| IL-13 | Th2 cells, basophils, eosinophils, mast cells, invariant NKT cells, type 2 ILCs | ↓ CTL-mediated tumor immunosurveillance via IL-4Rα/STAT6 signaling pathway.16 |
| IL-10 | B cells, CD4+ T cells | ↓ Th1 cell production of IL-2 and IFN-γ; ↑ B cell function; ↓ TAA cross-presentation by DCs; ↑ TGF-β–induced Treg generation and activation.12,13 |
| IL-6 | TAMs, MDSCs, CD4+ T cells, fibroblasts | ↓ Th1 differentiation of CD4+ T cells; ↓ DC maturation; ↑ generation of immune-suppressive alternatively activated (M2) macrophages and regulatory DCs; ↑ production of immune-suppressive factors (eg, IL-10, PGE2, and VEGF) by myeloid cells; ↑ STAT3 pathway, which induces angiogenesis, increases tumor invasiveness and metastasis, supports tumor cell survival, and promotes proliferation.7,8 |
| IL-11 | T cells, B cells, macrophages, osteoblasts, fibroblasts, chondrocytes | ↑ Tumorigenesis through activation of JAK/STAT3 signaling pathway.14 |
| IL-17 | Th17 cells | ↑ Tumor growth through IL-6/STAT3 signaling pathway; ↑ tumorigenesis (acting directly on transformed cells); ↑ tumor angiogenesis (through induction of angiogenic factors including VEGF, PGE2, and cytokines).55,123,124 |
Notes: ↑, promote; ↓, inhibit; cytokines promoting cancer progression are shown in italics.