Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 <i>In Vivo</i>

Dibra, Denada; Mitra, Abhisek; Newman, Melissa; Xia, Xueqing; Cutrera, Jeffry J.; Gagea, Mihai; Kleinerman, Eugenie S.; Lozano, Guillermina; Li, Shulin

doi:10.1158/1078-0432.ccr-15-2052

Cited by 17 publications

(14 citation statements)

References 22 publications

(22 reference statements)

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“…One of the most critical tumor suppressors, p53, is inherently instable and mutated in approximately 50% of tumors, and various stressors such as DNA damage or oncogenic activation such as RAS mutations can affect the oncogenic properties of the mutant p53 (46). Because IL-27 possesses anti-inflammatory and antitumor properties, the role of endogenous IL-27 signaling in the mutant p53-mediated tumorigenesis was investigated (47). Lack of IL-27 signaling was shown to decrease the survival and double the incidence of osteosarcoma, possibly due to increased stability of the mutant p53 protein expression, indicating that IL-27 signaling negatively modulates the oncogenic properties of mutant p53 in vivo (47).…”

Section: Interleukin-27mentioning

confidence: 99%

“…Because IL-27 possesses anti-inflammatory and antitumor properties, the role of endogenous IL-27 signaling in the mutant p53-mediated tumorigenesis was investigated (47). Lack of IL-27 signaling was shown to decrease the survival and double the incidence of osteosarcoma, possibly due to increased stability of the mutant p53 protein expression, indicating that IL-27 signaling negatively modulates the oncogenic properties of mutant p53 in vivo (47). In addition, lack of IL-27 signaling was demonstrated to cause spontaneous liver inflammation, fibrosis, and steatosis (48).…”

Section: Interleukin-27mentioning

confidence: 99%

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Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they comprise two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than six cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein–Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses, such as helper T (Th)1, Th2, and Th17, to anti-inflammatory responses, such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells, such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

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Section: Interleukin-27mentioning

confidence: 99%

Section: Interleukin-27mentioning

confidence: 99%

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

et al. 2016

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“…IL-27 is an IL-12 family cytokine that is known to inhibit autoimmune Th17 and Th2 responses (16,17). Accumulating evidence from animal studies has indicated that both endogenous (18,19) and exogenous (20)(21)(22) IL-27 inhibit tumor growth. A variety of mechanisms including enhancement of tumor-specific T cell responses (20,21) have been proposed.…”

Section: Introductionmentioning

confidence: 99%

IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy

Zhu¹,

Liu²,

Shi³

et al. 2018

JCI Insight

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Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.

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“…A key finding of this study is the tumor promoter activity of IL27 in the skin, and this discovery is surprising given that previous studies have attributed to IL27 anti-tumor activities mainly via eliciting an anti-immune response [11] [27–33]. Furthermore, in vitro studies suggest that IL27 promotes accumulation of Th1 response in keratinocytes via secretion of CXCL10 [34].…”

Section: Discussionmentioning

confidence: 93%

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

et al. 2016

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Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b−/− mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin—a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas.

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Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo

Cited by 17 publications

References 22 publications

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

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