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Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer

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Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer Juming Yan,1,2 Mark J. Smyth,2,3 and Michele W.L. Teng1,2 1Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia 2School of Medicine, University of Queensland, Herston 4006, Queensland, Australia 3Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia Correspondence: [email protected] The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy. he recognized interleukin (IL)-12 cytokine composition whereby the a-subunit (p19, Tfamily currently consists of IL-12, IL-23, p28, p35) and b-subunit (p40, Ebi3) are differ- IL-27, and IL-35 and these cytokines play im- entially shared to generate IL-12 (p40-p35), IL- portant roles in the development of appropriate 23 (p40-p19), IL-27 (Ebi3-p28), and IL-35 immune responses in various disease conditions (p40-p35) (Fig. 1A). Given their ability to share (Vignali and Kuchroo 2012). They act as a link a- and b-subunits, it has been predicted that between the innate and adaptive immune system combinations such as Ebi3-p19 and p28-p40 through mediating the appropriate differentia- could exist and serve physiological function tion of naı¨ve CD4þ T cells into various T helper (Fig. 1B) (Wang et al. 2012; Flores et al. 2015; (Th) subsets and regulating the functions of dif- Ramnath et al. 2015). Similarly, the subunit- ferent effector cell types. IL-12, IL-23, and IL-27 sharing feature of the IL-12 cytokine family are secreted byactivated antigen-presenting cells also extends to its receptor chain usage (Fig. (APCs), such as dendritic cells (DCs) and mac- 1B). Although they share structural similarities rophages (Vignali and Kuchroo 2012), whereas and downstream signaling components, mem- IL-35 is generally thought to be produced by bers of the IL-12 cytokine family mediate dis- regulatory T (Treg) and B cells, although they tinct biological functions. IL-12 and IL-23 are were recently detected in human tolerogenic proinflammatory cytokines and are required for DCs (Pylayeva-Gupta 2016). Aunique feature of the development of Th1 and Th17 cells (Vignali these cytokines is their heterodimeric subunit and Kuchroo 2012). In contrast, IL-27 has im- Editors: Warren J. Leonard and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028530 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press J. Yan et al. A IL-12 IL-23 IL-27 IL-35 p40 p35 p40 p19 Ebi3 p28 Ebi3 p35 1 1 β β 2 2 α β β IL-23R IL-12R IL-12R IL-12 IL-12 gp130 gp130 IL-27R TYK2 JAK2 TYK2 JAK2 JAK1 JAK2 JAK1 JAK2 STAT4 STAT3 STAT3 STAT4 STAT4 STAT4 STAT1 STAT1 B Ebi3 p19 p40 p28 1 β α IL-23R IL-12R gp130 IL-27R JAK1 JAK2 TYK2 JAK2 STA STAT3 T3 STAT1 STAT4 Figure 1. Schematic representation of the interleukin (IL)-12 cytokine family and their receptors, and associated Janus kinase and signal transducers and activators of transcription (JAK-STAT) signaling partners. (A) Current members of the IL-12 family with defined physiological function. (B) Potential new members of the IL-12 cytokine family that can be generated following subunit pairing. Ebi3, Epstein–Barr virus-induced gene 3 protein (also known as IL-27b); IL-12R, IL-12 receptor; IL-23R, IL-23 receptor; TYK2, tyrosine kinase 2. munosuppressive function and can curtail dif- and IL-23 in tumors can shape the development ferent classes of inflammation through its ability of antitumoror protumor immunity. Given that to directly modify CD4þ and CD8þ T-cell effec- the importance of IL-12 in promoting antitu- tor functions, to induce IL-10, and to promote mor immunity is well recognized and recently specialized Treg cell responses (Yoshida and reviewed (Tugues et al. 2015), this review will Hunter 2015). Likewise, IL-35 has an immuno- particularly focus on discussing the role of IL- suppressive function as shown by its ability to 23 in tumor biologyand its mechanism of action induce the development of IL-35-producing in- in promoting tumor growth and metastases. Fi- duced Tregs and the suppression of T-cell effec- nally, we discuss how IL-12 and IL-23 are cross- tor function and proliferative capacity in a vari- regulated and how the IL-12/IL-23 axis of in- ety of in vitro and in vivo systems (Vignali and flammation can be targeted for cancer therapy. Kuchroo 2012; Pylayeva-Gupta 2016). In cancer, inflammation has been shown to ROLE OF IL-12 AND IL-23 IN TUMOR play a critical role in tumor initiation, growth, BIOLOGY and metastasis (Grivennikov et al. 2010; Elinav et al. 2013). Itis nowappreciated that the balance APCs, such as DCs and macrophages, are between the proinflammatory cytokine IL-12 thought to be the predominant source of IL- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028530 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Roles of IL-12 and IL-23 in Cancer 12 and IL-23 (Hunter 2005). A major role of IL- croenvironment to be more conducive to anti- 12 is to promote differentiation of Th1 cells and tumor immunity by inhibiting angiogenesis and to induce type II interferon (IFN)-g produc- expanding intratumoral Tregs (Cao et al. 2009; tion. The requirement for host IL-12 and its Tugueset al. 2015). Nevertheless, IL-12may have downstream cytokine in activating antitumor IFN-g-independent tumor-suppressive proper- immunity is well recognized and has been pre- ties. A study using IL-12-producing B16 mela- viously reviewed extensively (Colombo and nomas, in which innate lymphoid tissue-induc- Trinchieri 2002; Dunn et al. 2006; Tugues et al. er cells but not T and NK cells induced tumor 2015). A number of studies have clearly illus- suppression (Eisenring et al. 2010), showed the trated the importance of endogenous IL-12 pleiotropic ability of IL-12 to activate multiple and IFN-g in preventing cancer initiation, arms of antitumor immunity. growth, and metastasis. In contrast, IL-23 plays The data that support the tumor-promoting an important role in promoting the prolifera- effect of host IL-23 is also strong. A seminal tion and effector function of Th17 cells, which paper by Langowski et al. (2006) provided the are characterized by expression of the IL-17 first demonstration that mice deficient in IL- family cytokines (Aggarwal et al. 2003; Langrish 23p19 were resistant to DMBA/TPA-induced et al. 2004; Langrish et al. 2005). Mice that were skin papillomas and this resistance correlated deficient for IL-12/23p40 or IFN-g and chal- with a significant increase in CD8þ T cells infil- lenged with methylcholanthrene-A (MCA), a trating the skin and a reduction in IL-17A, ma- chemical carcinogen, displayed increased rate trix metallopeptidase 9 (MMP9), CD31, gran- and frequency of tumor growth compared to ulocytes (Gr-1þ), and macrophages (CD11bþ, wild-type (WT) controls (Kaplan et al. 1998; F4/80þ). A study by Teng et al. (2010) further Smyth et al. 2000). In contrast, mice deficient confirmed the resistance phenotype of these in IL-23p19 were strongly protected from devel- mice to DMBA/TPA-induced skin papillomas oping MCA-induced fibrosarcomas (Teng et al. and also highlighted their resistance to MCA- 2010). In another study, using a mouse model of induced fibrosarcomas. Interestingly, IL-17A dimethylbenz[a]anthracene (DMBA)-initiated did not promote the formation of MCA-in- and 12-O-tetradecanoylphorbol-13-acetate duced fibrosarcomas, showing that IL-23p19 (TPA)-promoted two-stage skin carcinogenesis, had tumor-promoting properties independent IL-12/23p40-deficient and IL-23-p19-deficient of IL-17A (Teng et al. 2010). In contrast to the mice displayed significantly decreased numbers MCA model, mice deficient for IL-12/IL-23p40 of carcinogen-induced papillomas compared were still protected from tumor development to WTmice, whereas the opposite was observed following DMBA/TPA treatment, suggesting in IL-12p35-deficient mice (Langowski et al. in this model that the loss of IL-23 was more 2006). Similarly, mice lacking IL-12p35 and important than the loss of IL-12 (Teng et al. IFN-g were more susceptible to mortality 2010). In this model, Il17a-deficient mice dis- caused by N-methyl-N-nitrosourea (MNU)-in- played a protective phenotype albeit weaker duced lymphoma compared to IL-12/23p40- than Il23a-deficient mice. Furthermore, this deficient mice (Liu et al. 2004). Although naı¨ve study also showed that, not only did IL-23 sup- IL-12/23p40-deficient mice did not display any press the antitumor function of T cells as first increase in tumor development compared to uncovered by Langowski et al. 2006, it also sup- WT mice when monitored over their normal pressed the antimetastatic function of NK cells life span (Street et al.
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