Cytokines and soluble cytokine receptor induction after IL-12 administration in cancer patients

Haicheur, Nacilla; Escudier, Bernard; Dorval, Thierry; Négrier, Sylvie; Mulder, P.H.M. de; Dupuy, J. M.; Novick, Daniela; Guillot, T.; Wolf, Stanley F.; Pouillart, P; Fridman, Wolf‐Herman; Tartour, Éric

doi:10.1046/j.1365-2249.2000.01112.x

Cited by 64 publications

(62 citation statements)

References 58 publications

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“…In one study, cancer patients receiving increasing doses of IL-12 were profiled for changes in circulating cytokines after treatment [12]. Intriguingly, several potential immunosuppressive mechanisms were engaged upon repeated IL-12 administration, including a Th1 to Th2 shift as illustrated by an increase in IL-10 expression and diminishment of IFN-γ, tumor necrosis factor alpha (TNFα) and IP-10 in the sera of patients repeatedly treated with IL-12 [12,13]. As will be discussed later, this observation indicates a potential limitation for the use of IL-12 as a single agent.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy of cancer by IL-12-based cytokine combinations

Weiss

Subleski

Wigginton

et al. 2007

Expert Opinion on Biological Therapy

204

121

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Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/ or chemotherapy and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with tumor necrosis factor (TNF) alpha, type I or type II Interferons (IFNs), Interleukins (IL)-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of pre-clinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27, and their immunomodulatory and anti-tumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines, but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of preclinical data that convincingly demonstrate synergistic and/or novel biological effects that may be achieved through the use of several combinations of cytokines with complementary immunestimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anti-cancer effects, and synergizes with several other cytokines for increased immunoregulatory and anti-tumor activities. This review will discuss the anti-tumor activity of IL-12, with a special emphasis on its ability to synergize with other cytokines for enhancement of immune effector cell populations and regulation of host-tumor cell interactions and the overall tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Immunotherapy of cancer by IL-12-based cytokine combinations

Weiss

Subleski

Wigginton

et al. 2007

Expert Opinion on Biological Therapy

204

121

View full text Add to dashboard Cite

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“…A paradigmatic scenario occurring in IL-12-mediated tumor rejection involves the cytotoxicity of CD8 ϩ cells, the Th1 differentiation of naive CD4 ϩ cells that can subsequently provide help for tumor-specific priming of CTLs, and an antiangiogenic effect. It has been shown that the IL-12 effect is largely mediated in vivo by IFN-␥ and its correlate molecules CXCL10 and CXCL9 (26,(32)(33)(34). Our experiments confirm the key role of the IFN-␥-CXCL9/CXCL10 axis in the effect of IL-12, but also add new details describing a reciprocal paracrine loop existing between ECs and stimulated PBMC that is regulated by CXCL9 and CXCL10 and does not require the presence of tumor cells as the source of these chemokines (24,49,60,61).…”

Section: Discussionmentioning

confidence: 99%

“…The indirect biologic effects of IL-12 on ECs are mainly exerted by the production of IFN-␥, which in turn stimulates that of CXCL10 and CXCL9 (23,29,(32)(33)(34)(47)(48)(49)(50)(51). In our system, stimulated PBMC either alone or cocultured with ECs produced IFN-␥ transcript as evaluated by RT-PCR.…”

Section: Cxcl9 and Cxcl10 Alter Mmp9 Activity In Ecs And Chemoinvasiomentioning

confidence: 94%

“…Furthermore, an early effect of IL-12 on tumor behavior is inhibition of angiogenesis, resulting in ischemic necrosis (22,24,(27)(28)(29)(30)(31). These effects are primarily dependent on the release of TNF-␣ and IFN-␥, which modulates the induction of downstream chemokines IFN-␥-inducible protein 10 (CXCL10) and monokine induced by IFN-␥ (CXCL9) (26,(32)(33)(34). We recently demonstrated that coculture of human ECs in the presence of IL-12-stimulated lymphocytes resulted in the inhibition of in vitro angiogenesis and of induction of MMP9 in ECs.…”

Section: Il-12 Regulates An Endothelialmentioning

confidence: 99%

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IL-12 Regulates an Endothelial Cell-Lymphocyte Network: Effect on Metalloproteinase-9 Production

Mitola¹,

Strasly²,

Prato³

et al. 2003

The Journal of Immunology

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IL-12 is key cytokine in innate immunity and participates in tumor rejection by stimulating an IFN-γ-mediated response characterized by CD8+ mediated-cytotoxicity, inhibition of angiogenesis, and vascular injury. We previously demonstrated that activated lymphocytes stimulated with IL-12 induced an angiostatic program in cocultured vascular endothelial cells. In this study, we have extended this observation showing that a reciprocal modulation of cellular responses occurs. Actually, the presence of endothelial cells enhanced the inhibitory effect of IL-12 on metalloproteinase-9 expression in activated PBMC as well as their ability to transmigrate across an extracellular matrix. IL-12 triggered intracellular signaling, as indicated by STAT-1 activation, appeared to mainly operative in activated CD4 + cells challenged with IL-12, but it was also initiated in CD8+ lymphocytes in the presence of endothelial cells. On the other hand, stimulated PBMC reduced the expression and the activity of metalloproteinase-9, up-regulated that of tissue inhibitor metalloproteinase-1, and stimulated the STAT-1 pathway in cocultured endothelial cells. We used neutralizing Abs to show that the IFN-inducible protein 10 (CXCL10) and monokine-induced by IFN-γ (CXCL9) chemokines produced by both PBMC and endothelial cells are pivotal in inducing these effects. Altogether these results suggest the existence of an IL-12-regulated circuit between endothelium and lymphocytes resulting in a shift of proteolytic homeostasis at site of tissue injury.

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“…IL-12 primarily exerts its anti-tumor effect via indirect interaction with tumor cells by stimulating potent cytokines such as IFN-␥ and TNF-␣. 11 We, therefore, determined the induced production of IFN-␥ and TNF-␣ at 48 h after injection of PAGA/pmIL-12 complexes into CT-26 subcutaneous tumor-bearing BALB/c mice to see whether IL-12 was able to up-regulate these two cytokines. Similar trends were found in both cases (Figures 2 and 3).…”

Section: Gene Expression For Induced Cytokinesmentioning

confidence: 99%