JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Abstract

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.

Keywords: JAK; STAT; cancer; immunosurveillance; inflammation; interferons; signaling.

Figure 1

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways (simplified). Cytokine signaling occurs through various JAK-STATs. (a) Canonical type II IFN signaling occurs through receptors, IFNGR1 and IFNGR2, which constitutively associate with JAK1 and JAK2, respectively, leading to the phosphorylation of STAT1. Phosphorylated STAT1 homodimers translocate to the nucleus and bind to GAS elements, initiating the transcription of IFN-γ induced genes associated with immune activation. IFN-γ signaling can also lead to the phosphorylation of STAT3, which forms homo- or heterodimers that bind to GAS elements to induce inflammatory genes. (b) The type I IFN pathway can be stimulated by multiple family members, the most well-known being IFN-α and IFN-β. The receptors IFNAR1 and IFNAR2 are associated with TYK2 and JAK1, respectively. Canonical type I IFN signaling occurs through the phosphorylation of STAT1 and STAT2, which, together with IRF9, form the ISGF3 complex. ISGF3 translocates to the nucleus to initiate the transcription of IRGs through the ISRE regulatory sequence. Non-canonical type I IFN signaling can occur through the CRKL or NFκB pathway. Subsequent to JAK activation, CRKL can become phosphorylated by TYK2, which leads to CRKL complexation with STAT5, which then binds GAS elements in the nucleus. (c) IFNAR1/2 signaling through TYK2 and JAK1 can trigger the activation of the NFκB pathway through phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs) that act through IKKa and IKKb to drive NFκB induction of genes associated with survival and cell proliferation. The production of type I IFNs can also occur through activation of PRRs that converge on IRF7 to promote further production of type I IFNs and viral response genes. (d) Cytokines, both pro- and anti-inflammatory, signal through their associated receptor/JAK complexes, resulting in the downstream phosphorylation of STATs (homo- or heterodimers). Translocation of these STAT complexes to the nucleus drives the transcription of genes involved in processes ranging from inflammation to angiogenesis and survival. Abbreviations: JAK, Janus kinase; STAT, signal transducer and activator of transcription; IFN, interferon; IFNGR, interferon gamma receptor; GAS, gamma activated sequence; IFNAR, interferon alpha receptor; ISGF3, interferon-stimulated gene factor 3; ISRE, interferon-stimulated response element; TYK2, tyrosine kinase 2; NFκB, nuclear factor kappaB; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; TRAF, TNF receptor-associated factor; PRR, pattern recognition receptor.

Figure 2

STAT signaling in the tumor microenvironment (TME). Tumor cell fate is governed by tumor-inherent properties and the activity of surrounding immune cells, both of which are influenced by JAK-STAT signaling. A protumor immune microenvironment reflects a permissive niche and is comprised of populations including Th2 and Th17 cells, Tregs, and myeloid-derived suppressor cells (MDSCs), which signal mainly through STAT3 and STAT5 to produce inflammatory cytokines, such as IL-1, IL-17, IL-10, TGF-β, or vascular endothelial growth factor (VEGF). These cytokines can inhibit antitumor immune responses, promote TME suppression and act directly on tumor cells. High tumor cell STAT3 promotes tumor growth and metastasis, inhibits STAT1 signal transduction and leads to the production of protumor chemokines, cytokines and growth factors. Antitumor immune signaling is largely facilitated by cells involved in antigen recognition and directed cancer cell killing. Th1 cells, CD8 T cells, natural killer (NK) cells, and dendritic cells (DCs) are all involved in antitumor immune responses through the secretion of cytokines, such as IFN-α/β, IFN-γ, TNF-α, and IL-2, along with perforins and granzymes, that induce tumor cell apoptosis, necrosis, T cell priming and antigen presentation. Cell-specific function and selective cytokine production is mainly regulated through STAT1 and STAT4. Acting on the tumor cell, these cytokines can signal through STAT1 to promote tumor immunogenicity via the upregulation of MHC and checkpoint proteins. Tumor cells themselves can also produce immune-stimulating cytokines, such as type I IFNs, to further promote immune infiltration and tumor visibility. Abbreviations: JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th, T-helper; Treg, regulatory T cell; MDSCs, myeloid-derived suppressor cells; IL, interleukin; TGF-β, transforming growth factor-beta; VEGF, vascular endothelial growth factor; TME, tumor microenvironment; NK, natural killer; DC, dendritic cell; IFN, interferon; TNF-α, tumour necrosis factor-alpha; MHC, major histocompatibility complex; GM-CSF, granulocyte-macrophage colony stimulating factor; PD-L1, programmed death-ligand 1.