TYK2 in Tumor Immunosurveillance

Abstract

We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue 'Targeting STAT3 and STAT5 in Cancer' of Cancers.

Keywords: Janus kinase (JAK) family; STATs; cancer-immunity cycle; immunoediting; interferons; interleukins; tyrosine kinase 2.

Figure 1

Simplified scheme of the cancer-immunity cycle and the involvement of TYK2, focusing on innate and adaptive immune cells in tumor surveillance and the feedforward loops in the TYK2-dependent cytokine responses and production. Type II IFN and IL-15 production largely depends on TYK2, while the cytokine receptors signal independently of TYK2. Type I and III IFNs, IL-12 and IL-23 act through TYK2-dependent receptors, with an amplification of type I and III IFN production by TYK2 signaling. Effects of the cytokines on shaping the TME and the stroma cells are reviewed elsewhere [19,115,116]. CR, cytokine receptor; CR-TYK2, TYK2-dependent cytokine receptor; DAMPs, danger-associated molecular patterns; IFNα, type I IFN; IFNγ, type II IFN; IFNλ, type III IFN; IFNLR, receptor for type III IFN, IFNλ; IL12R, receptor for family members IL-12 or IL-23; IL15R, simplified for IL-15 responses through IL-15/IL-15 Rα trans-presentation or soluble IL-15 binding to IL-15Rβ/γ_C/IL-15Rα (see text); TYK2 cytokines, cytokines depending on TYK2 with respect to signaling and/or production. The figure was compiled with Servier Medical Art (https://smart.servier.com).