Cytokines in cancer

Abstract

Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.

Keywords: IFN-α; IFN-γ; IL-2; JAK; TGF-β; TNF-α; chemokine; cytokine; interferon; interleukin.

Figure 1.. Modes of cytokine activity

Autocrine signaling occurs when cytokines are secreted by a cell that expresses the receptor for that same cytokine. Paracrine signaling occurs when cytokines are secreted by one cell type and received by a different cell type expressing the receptor. In rare cases, cytokines signal systemically and exert long range effects on other organs in the body such as the central nervous system, liver, or bone marrow. Chemokines (depicted in orange) are a subset of cytokines regulating cell migration and are deposited in gradients within tissues or along endothelial cells. Responding cells can internalize the chemokine receptors to desensitize signaling in areas of high chemokine concentration.

Figure 2.. Overview of cytokine signaling

Many cytokines signal by inducing dimerization of two receptor chains. Receptor dimerization brings JAKs near each other, leading to phosphorylation of the receptors, the JAKs, and STATs. Several cytokine receptor families form higher order complexes consisting of dimers of the ligand and receptor chains. These include the IL-10 family, the common beta chain cytokine family (IL-3, IL-5, GM-CSF), and the IL-6 family.^, Cytokines depicted are clustered into structural families that use shared or homologous receptor subunits. Receptor heterodimers are depicted in different shades of the same color. Phosphorylation sites are shown in orange. SH2 domains are shown in blue. Ligand binding leads to JAK phosphorylation. Cytokine receptors also become phosphorylated at STAT binding sites. After binding to cytokine receptor tail, STATs become phosphorylated and then dimerize. STAT dimers translocate to the nucleus and activate gene transcription. TGF-β receptor ligation leads to R-SMAD phosphorylation. Phosphorylated R-SMAD activates and binds to SMAD4, and together the R-SMAD:SMAD-4 complex activates transcription in the nucleus. IL-1 family receptors contain TIR domains, which dimerize upon ligand binding. TIR domain dimerization recruits MyD88, IRAK, and other adaptor proteins. Together, this signaling leads to the degradation of IkB and the release of NF-κB subunits which dimerize and translocate to the nucleus to activate gene transcription. TNF superfamily members signal through a pre-assembled trimeric receptor to NF-κB as well, but they can also induce caspase-8 (CASP8) activation and apoptosis.^,

Figure 3.. IFN-γ plays a central role in anti-tumor immunity

Diagram shows a tumor cell in dark blue presenting antigen on MHC class I to a CD8⁺ T cell. A nearby macrophage in green is ready to engulf the tumor cell and present antigen on MHC-II to a CD4⁺ T cell. IFN-γ is secreted by CD8⁺ and CD4⁺ T cells, and it can enhance multiple steps: (1) activation of NLRC5 and increased transcription of genes encoding MHC class I and antigen processing machinery, such as TAP1/2, tapasin, and ER chaperones; (2) switching the proteasome subunits to form the less efficient immunoproteasome to generate longer peptides; (3) increased activation of CIITA and transcription of genes encoding MHC class II and lysosomal proteases, such as GILT; (4) increased mobilization of peptide-loaded MHC class II to the cell surface; and (5) increased phagocytosis. IFN-γ also induces expression of the negative regulatory ligand PD-L1. CD4 T cell CD40L binding to macrophage CD40 stimulates macrophage NF-κB signaling.