Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model

Canale, S; Cocco, Claudia; Frasson, Chiara; Seganfreddo, Elena; Carlo, Emma Di; Ognio, Emanuela; Sorrentino, Carlo; Ribatti, Doménico; Zorzoli, Alessia; Basso, Giuseppe; Dufour, Carlo; Airoldi, Irma

doi:10.1038/leu.2011.158

Cited by 57 publications

(47 citation statements)

References 38 publications

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“…In some hematologic neoplasia, including multiple myeloma (45) and acute leukemias (46,47), IL-27 displays direct and indirect antitumor effects. We thus hypothesize that in EOC IL-27 may be part of an immune-regulatory network, which limits the induction of T H 1 responses and IFN-g production in the microenvironment by inhibiting IL-18 activity.…”

Section: Discussionmentioning

confidence: 99%

The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

Carbotti

Barisione

Orengo

et al. 2013

Clinical Cancer Research

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Purpose: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-g production, T-helper 1 responses, and antitumor effects. In turn, IFN-g stimulates IL-18-binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo.Experimental Design: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients' serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR.Results: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3 À CD20EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-g stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity.

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Section: Discussionmentioning

confidence: 99%

The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

Carbotti

Barisione

Orengo

et al. 2013

Clinical Cancer Research

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“…The IL-27R contains the unique receptor subunit WSX-1, also known as IL-27Ra/TCCR, paired with the gp130 chain (5,6). Although IL-27R was found to be expressed on different human hematologic malignancies (7,8), no information is available on the role played by IL-27 on pediatric AML cells.…”

Section: Introductionmentioning

confidence: 99%

“…It has also been reported that IL-27 can directly inhibit the proliferation of human melanoma cell lines (15), suppresses tumorigenicity and invasiveness of human lung adenocarcinoma cell lines (16), and dampens multiple myeloma cell growth in vivo, inhibiting osteoclast differentiation and function and inducing osteoblast proliferation (8). In addition, we recently reported that IL-27 inhibits B-acute lymphoblastic leukemia (ALL) cell spreading in animal models (7).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 Inhibits the Growth of Pediatric Acute Myeloid Leukemia in NOD/SCID/Il2rg−/− Mice

Zorzoli

Carlo

Cocco

et al. 2012

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) accounts for more than half of fatal cases in all pediatric leukemia patients; this observation highlights the need of more effective therapies. Thus, we investigated whether interleukin (IL)-27, an immunomodulatory cytokine, functions as an antitumor agent against pediatric AML cells.Experimental Design: Expression of WSX-1 and gp130 on AML cells from 16 pediatric patients was studied by flow cytometry. Modulation of leukemia cell proliferation or apoptosis upon IL-27 treatment in vitro was tested by bromodeoxyuridine/propidium iodide (PI) and Ki67, or Annexin V/PI staining and flow cytometric analysis. The angiogenic potential of AML cells treated or not with IL-27 was studied by chorioallantoic membrane assay and PCR array. In vivo studies were carried out using nonobese diabetic/ severe combined immunodeficient (NOD/SCID)/Il2rg À/À mice injected intravenously with five pediatric AML cell samples. Leukemic cells engrafted in PBS and IL-27-treated animals were studied by immunohistochemical/morphologic analysis and by PCR array for expression angiogenic/dissemination-related genes. Results: We provided the first demonstration that (i) AML cells injected into NOD/SCID/Il2rgÀ/À mice gave rise to leukemia dissemination that was severely hampered by IL-27, (ii) compared with controls, leukemia cells harvested from IL-27-treated mice showed significant reduction of their angiogenic and spreading related genes, and (iii) similarly to what was observed in vivo, IL-27 reduced in vitro AML cell proliferation and modulated the expression of different genes involved in the angiogenic/spreading process. Conclusion: These results provide an experimental rationale for the development of future clinical trials aimed at evaluating the toxicity and efficacy of IL-27.

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“…In addition, we recently demonstrated that IL-27 acts as multifunctional anti-tumor agent in multiple myeloma (MM) 22 and inhibits acute lymphoblastic leukemia cell spreading in a pre-clinical model. 32 With this background, we here investigated (i) the expression of both chains of IL-23 and IL-27 R in human primary FL and DLBCL cells and cell lines, (ii) the potential anti-tumor activities of IL-23 and IL-27 against FL and DLBCL cells and (iii) the mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%

Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo

Cocco

Carlo

Zupo³

et al. 2011

Leukemia

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Interleukin (IL)-23 and IL-27 are pro-inflammatory cytokines that share functional and structural similarities and may exert anti-tumor activities against solid and hematological malignancies. Here, we asked whether IL-23 and IL-27, alone or in combination, may act directly against human follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) cells.In this study, we demonstrated for the first time that human primary FL and DLBCL cells expressed complete and functional IL-23 and IL-27 receptors (R) and that IL-23 and IL-27 exerted anti-tumor activities in vitro and in vivo through different and complementary mechanisms. In vivo studies using severe combined immunodeficiency /non-obese diabetic mice-injected subcutaneously with human SU-DHL-4 cell line revealed that IL-23 inhibited directly tumor-cell proliferation, whereas IL-27 impaired the angiogenic program of lymphoma cells resulting in strong reduction of cell growth. In addition, combined treatment of IL-23 and IL-27 amplified the anti-tumor effects in vivo as compared with administration of each cytokine alone. These anti-tumor mechanisms were confirmed by in vitro experiments performed with primary lymphoma cells and cell lines. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of the IL-23 and IL-27 in lymphoma patients.

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Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model

Cited by 57 publications

References 38 publications

The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

Interleukin-27 Inhibits the Growth of Pediatric Acute Myeloid Leukemia in NOD/SCID/Il2rg−/− Mice

Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo

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