Trends in Immunology
ReviewA balance of interleukin-12 and -23 in cancer
Section snippets
IL-12 and IL-23
The IL-12 cytokine family is consisting of IL-12, IL-23, IL-27, and IL-35. These are heterodimeric cytokines formed by two subunits [1]. IL-27 is formed by the pairing of the Ebi3 and p28 subunits, whereas IL-35 is formed by the pairing of Ebi3 and p35 subunits. The pairing of p19 subunit with p40 subunit forms IL-23, whereas the pairing of the p35 and p40 subunits forms IL-12 1, 2, 3 (Figure 1). IL-12 receptor (IL-12R) is composed of IL-12Rβ1 and IL-12Rβ2, whereas IL-23 receptor (IL-23R) is
IL-12 in tumor immunity
Although there are similarities between IL-12 and IL-23, there is increasing evidence that these cytokines modulate divergent immunological activities. Other than promoting the cytotoxic function of NK cells, IL-12 drives the development of Th1 cells via the activation of STAT4. These cytotoxic IFN-γ-producing Th1 cells are crucial for antimicrobial and antitumor responses [7]. The role of IL-12 and its downstream cytokine IFN-γ in antitumor immunity has been demonstrated 8, 9 and extensively
IL-23 in immune responses
By contrast, IL-23 is crucial for the development of Th17 cells, a distinct lineage of CD4+ T cells, characterized by their production of signature cytokines IL-17A, IL-17F, and occasionally IL-21 and IL-22 23, 24. Endogenous Th17 cells mediate antimicrobial and antifungal responses, or in a pathogenic form, promote autoimmune diseases [23]. IL-23-driven IL-17-producing cells (Th17 cells and IL-17-producing innate cells) are generally essential for an antimicrobial response 3, 4, 5, 25. IL-23
Regulation of IL-12 and IL-23 production
DCs and macrophages are thought to be the main producers of IL-12 and IL-23 in response to Toll-like receptor (TLR) stimulation by pathogen and viral components and/or via CD40–CD40 ligand (CD40L) signaling 2, 3, 32, 33, 34. What are the factors that induce DCs or macrophages to produce the appropriate cytokines to drive an inflammatory response? It is unlikely that there is a distinct population of naïve DCs or macrophages that are programmed to secrete either IL-12 or IL-23 upon infection or
IL-23 production in a tumor context
What about stimuli for IL-23 in a tumor context? Recently, in an inflammation- and mutated Apc (adenomatous polyposis coli)-driven colorectal cancer model, it was found that gut microbial products induced IL-23 secretion from a population of CD11b+ myeloid cells, whereas IL-23 was also secreted by a population of CD11b– immune cells in the tumor microenvironment. Although the identity of these IL-23-producing CD11b– immune cells has not been fully defined, IL-23 signaling induced a protumor
Tumor-initiating properties of IL-23
The role of IL-23 in promoting tumorigenesis (Table 1) was first demonstrated in experiments using IL-23p19-deficient mice that were found to be almost completely resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol acetate (TPA)-induced skin papillomas [20]. This study reported a significant increase in CD8+ T cells infiltrating the DMBA/TPA-treated skin of IL-23p19-deficient mice compared to wild type control mice. This was also accompanied by a reduction in IL-17,
Tumor-suppressing properties of IL-23
In contrast to the role of endogenous IL-23 in promoting tumorigenesis, there have been some studies suggesting that IL-23 can potentially promote an antitumor effect (Table 2). For example, independent studies have demonstrated that mouse tumor cell lines engineered to overexpress IL-23 have impaired tumor growth in vivo 71, 72, 73. Others have reported that the administration of high-dose IL-23, IL-23-expressing adenovirus, or IL-23-expressing DCs or bone-marrow-derived neural-like stem cells
Clinical observations concerning IL-12 and IL-23
Clinical observations have established that IL-12/23p40 is integral to the pathologies of psoriasis, psoriatic arthritis, and Crohn's disease (Figure 2). Ustekinumab (anti-IL-12/IL-23) is the first market-approved member of a new biological therapy family targeting IL-12 and IL-23 [85]. The molecular and cellular evaluations conducted for ustekinumab clinical programs provide insight into the pathology of these disorders, illustrating how a novel molecular entity can contribute to our
Concluding remarks
It should be appreciated that interpretation of mouse studies are complicated by the potential differences between mouse and human IL-12 and IL-23 biology. For example, pharmacological dosing of recombinant IL-12 has demonstrated efficacy in mouse tumor models, but has not translated to safe or efficacious therapy in humans. Also, recent findings suggest that Th cells are regulated differently in mice than in humans [94]. Given the species differences in IL-12 and IL-23 biology, it is difficult
Acknowledgments
The authors wish to thank Dr. Jennifer Towne (AMGEN) for helpful discussions. SFN was supported by a Cancer Research Institute PhD scholarship. MJS was supported by a National Health and Medical Research Council of Australia (NH&MRC) Program Grant and Australia Fellowship. MWLT was supported by a NH&MRC CDF1 Fellowship.
References (99)
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12
Immunity
(2000)Cytokine-induced cytokine production by conventional and innate lymphoid cells
Trends Immunol.
(2012)Lymphoid microenvironments and innate lymphoid cells in the gut
Trends Immunol.
(2012)- et al.
Interleukin-12 in anti-tumor immunity and immunotherapy
Cytokine Growth Factor Rev.
(2002) Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy
Blood
(2005)Understanding the IL-23-IL-17 immune pathway
Trends Immunol.
(2006)Innate IL-17 and IL-22 responses to enteric bacterial pathogens
Trends Immunol.
(2012)Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity
Immunity
(2009)Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages
J. Biol. Chem.
(2012)Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity
Immunity
(2009)
CD40 ligand-triggered human dendritic cells mount interleukin-23 responses that are further enhanced by danger signals
Mol. Immunol.
Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology
Immunity
Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway
Blood
TLR8 and NOD signaling synergistically induce the production of IL-1beta and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2
Immunobiology
Immunity, inflammation, and cancer
Cell
60-kDa heat shock protein of Chlamydia pneumoniae promotes a T helper type 1 immune response through IL-12/IL-23 production in monocyte-derived dendritic cells
Microbes Infect.
Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment
Cancer Cell
Activation and effector functions of human RORC+ innate lymphoid cells
Curr. Opin. Immunol.
IL-17 and IL-22: siblings, not twins
Trends Immunol.
IL-12 and IL-23 affect photocarcinogenesis differently
J. Invest. Dermatol.
IL-23 antagonizes UVR-induced immunosuppression through two mechanisms: reduction of UVR-induced DNA damage and inhibition of UVR-induced regulatory T cells
J. Invest. Dermatol.
Elevated serum level of IL-23 correlates with expression of VEGF in human colorectal carcinoma
Arch. Med. Res.
IL-23 is pro-proliferative, epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer
Lung Cancer
Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma
Mol. Immunol.
Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells
Blood
High IL-12 p35 and IL-23 p19 mRNA expression is associated with superior outcome in ovarian cancer
Gynecol. Oncol.
Swords into plowshares: IL-23 repurposes tumor immune surveillance
Trends Immunol.
Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials
J. Am. Acad. Dermatol.
A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis
J. Invest. Dermatol.
Malignancy concerns with psoriasis treatments using phototherapy, methotrexate, cyclosporin, and biologics: facts and controversies
Clin. Dermatol.
Antitumor effects and immunoregulation mechanisms of IL-23 gene in mouse mammary cancer mediated by retrovirus
Cell. Immunol.
IL-12 family cytokines: immunological playmakers
Nat. Immunol.
Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation
Annu. Rev. Immunol.
Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells
J. Immunol.
Interleukin-12 and the regulation of innate resistance and adaptive immunity
Nat. Rev. Immunol.
Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production
J. Immunol.
Interleukin 12 stimulates IFN-gamma-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance
Cancer Res.
Interferons, immunity and cancer immunoediting
Nat. Rev. Immunol.
IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors
J. Clin. Invest.
IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46
Nat. Immunol.
Differential tumor surveillance by natural killer (NK) and NKT cells
J. Exp. Med.
Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice
Proc. Natl. Acad. Sci. U.S.A.
Interleukin-12 activates NK cells for IFN-gamma-dependent and NKT cells for IFN-gamma-independent antimetastatic activity
Eur. Cytokine Netw.
Immunity to Chlamydia trachomatis is mediated by T helper 1 cells through IFN-gamma-dependent and -independent pathways
J. Immunol.
Interferon gamma-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major
Proc. Natl. Acad. Sci. U.S.A.
IFN-gamma-independent effects of IL-12 during intestinal nematode infection
J. Immunol.
IL-23 promotes tumour incidence and growth
Nature
Suppression of lymphoma and epithelial malignancies effected by interferon gamma
J. Exp. Med.
IL-17 and Th17 Cells
Annu. Rev. Immunol.
Cited by (91)
Anti-PADI4 antibody suppresses breast cancer by repressing the citrullinated fibronectin in the tumor microenvironment
2022, Biomedicine and PharmacotherapyCitation Excerpt :IL-23 promotes tumor growth and metastasis. IL-12 and IL-23 can be targeted for cancer therapy [22–25]. Decreased hemoglobin levels were significantly associated with poor overall survival in patients with non-small-cell lung cancer and small cell lung cancer [26–28].
TRAF6-overexpressing dendritic cells loaded with MUC1 peptide enhance anti-tumor activity in B16-MUC1 melanoma-bearing mice
2022, International ImmunopharmacologyCitation Excerpt :Mature DCs can improve their ability to stimulate T cell activation and secrete the cytokine IL-12. In the process of T-cell priming, the presence of IL-12 not only induces Th1 differentiation, but also inhibits Th2 differentiation [21]. IL-12 enhances IFN-γ and granzyme B production, prolongs the survival of T cells, and improves the recognition of tumor antigen-expressing cells [22].
The Relapse of Psoriasis: Mechanisms and Mysteries
2022, JID InnovationsiNKT: A new avenue for CAR-based cancer immunotherapy
2022, Translational OncologyCitation Excerpt :Recent preclinical studies proved that STAT3 signaling pathway enhances the efficacy of CAR-T against patients with chronic lymphoblastic leukemia [79,80]. IL-23 can promote the proliferation of memory T cells through activating STAT3 pathway [81,82] . Ma.X et al. found that IL-23 can also provide a strong selective proliferation signal for CAR-T in tumor microenvironment [82].
Cancer risks in patients with psoriasis administered biologics therapy: a nationwide population-based study
2023, Journal of Cancer Research and Clinical OncologyGenetically modified cancer vaccines: Current status and future prospects
2022, Medicinal Research Reviews