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Review
. 2017 Apr;108(4):574-580.
doi: 10.1111/cas.13194. Epub 2017 Apr 19.

Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Affiliations
Review

Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy

Shunsuke Chikuma et al. Cancer Sci. 2017 Apr.

Abstract

Inhibition of immune checkpoint molecules, PD-1 and CTLA4, has been shown to be a promising cancer treatment. PD-1 and CTLA4 inhibit TCR and co-stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon-γ (IFNγ) plays an important role in anti-tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti-tumor immunity and potential applications.

Keywords: Immune checkpoint; JAK-STAT; T cell; kinase inhibitory region; suppressors of cytokine signaling.

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Figures

Figure 1
Figure 1
T cell immune checkpoints for anti‐tumor immunity. There are three major T cell activation signals, signal 1, signal 2 and signal 3. Signal 1 is MHC‐antigen‐peptide complex‐TCR signal that activate tyrosine kinases including ZAP70. Signal 2 is the co‐stimulatory signals from CD28, in which mostly PI3 kinase is involved. Signal 3 is the cytokine receptor signals that activate the JAK/STAT pathway. T cell activation by TCR, co‐simulators, and cytokines is blocked by (1) PD‐1, (2) CTLA4, and (3) SOCS.
Figure 2
Figure 2
General mechanism of the action of CIS, SOCS1, and SOCS3. Cytokine stimulation activates the JAKSTAT pathway, leading to the induction of CIS, SOCS1 and/or SOCS3. SOCS1 binds to the JAKs and inhibits catalytic activity, SOCS3 binds to JAK‐proximal sites on cytokine receptors and inhibits JAK activity, and CIS blocks the binding of STATs to cytokine receptors and induces receptor degradation.
Figure 3
Figure 3
Structure of the complex of JAK2 and SOCS3, and pg130 phosphopetide. SOCS3 binds the kinase domains of JAK1, JAK2, and TYK2 and inhibits its catalytic activity by blocking the substrate‐binding site with its kinase inhibitory region. SOCS3 remains bound to gp130 while in complex with JAK (beige). Regions for GQM motif and KIR are highlighted. The figure is from Babon JJ, Varghese LN, and Nicola NA. Inhibition of IL‐6 family cytokines by SOCS3. Semin Immunol. 2014; 26: 13–19.61 Permission was obtained from Dr. Babon.
Figure 4
Figure 4
Anti‐tumor activity of myeloid cell‐specific SOCS1 conditional knockout ( cKO ) mice. WT,SOCS1cKO,IFNγ−/− and SOCS1 −/− IFNγ−/− mice were subcutaneously challenged with B16 melanoma cells. Kaplan–Meier survival curves are depicted as time after tumor challenge. Data are modified from Hashimoto et al. Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation. Cancer Science. 2009; 100: 730–736.45 Copyright (c) (2009) AY.
Figure 5
Figure 5
Effects of KIR mutations on IFNγ‐STAT1 activation. Transgenic thymocytes loading a point mutation in KIR domain which does not interact with JAK GQM motif exhibited prolonged STAT1 activation induced by IFNγ stimulation. This research was originally published in the Journal of Biological Chemistry [A mutant form of JAB/SOCS1 augments the cytokine‐induced JAK/STAT pathway by accelerating degradation of wild‐type JAB/CIS family proteins through the SOCS‐box. J Biol Chem. 2001; 276: 40746–54].60
Figure 6
Figure 6
Model of the effect of a SOCS inhibitor for JAK tyrosine kinase activity. A hypothetical SOCS inhibitor which blocks interaction between KIR region of SOCS1 and GQM motif of JAK will inhibit the action of KIR, therefore the substrate is accessible to the catalytic pocket of JAK. Furthermore, binding of SOCS1‐SH2 domain may protect dephosphorylation of JAK's “kinase activation loop”; therefore, the kinase activation will be prolonged.

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