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ERC

CYRE Report Summary

Project ID: 340941
Funded under: FP7-IDEAS-ERC
Country: Belgium

Mid-Term Report Summary - CYRE (Cytokine Receptor Signaling Revisited: Implementing novel concepts for cytokine-based therapies)

The central, overarching theme of the CYRE ERC advanced grant is cytokine receptor signaling. We seek to gain novel insights in how cytokines activate their cognate receptors and how the resulting signals are modulated to enable optimally tuned cellular and physiological responses. The program aims at advancing both fundamental and applied medical sciences, since many human pathologies, including cancer and auto-immune diseases, are linked to dysfunctional cytokine signaling.

Our approaches are based on several in-house developed novel technologies that allow studying both extra- and intracellular aspects of cytokine receptor functioning. Key objectives include (i) development of AcTakines, a novel class of cell-targeted immunocytokines, (ii) elucidating alternative receptor activation mechanisms using the leptin receptor as a model, (iii) building (dynamic) intracellular signaling interactome maps using optimized MAPPIT/KISS and Virotrap toolboxes.

The major aim of Objective 1 is the in vivo evaluation of AcTakines (Activity-on-Target cytokines). We demonstrated that highly specific cell targeting can be achieved, thus completely eliminating systemic toxicity. Proof-of-concept was obtained for structurally very different cytokines such as type 1 interferons (IFNs), Tumor Necrosis Factor (TNF) and interleukin-& (IL-1), indicating the broad applicability of the approach. In vivo studies in different murine tumor models showed high anticancer efficacy of tumor- or immune cell-targeted IFNs (AcTaferons). In co-treatment regimens, e.g. with doxorubicin or checkpoint inhibitors, cancer cures could be obtained. Similarly, strong beneficial effects were also obtained in an EAE mouse model for multiple sclerosis, again with no detectable off-target toxicity effects.

In Objective 2, we are investigating non-canonical leptin receptor signaling. Both biochemical and genetic evidence was obtained that leptin signaling can be uncoupled at the receptor level. Molecular understanding of the underlying mechanism should pave the way to the development of selective antagonists that interfere with this cross-talk in immune cells (e.g. in autoimmune disorders) without affecting the central role of leptin as regulator of body weight and metabolic homeostasis.

The central theme of Objective 3 is the development and application of high-throughput technologies to chart intracellular pathways relevant to cytokine receptor functioning. Key to this endeavor is the detection of protein-protein interactions (PPIs). The MAPPIT platform was originally developed in our laboratory and allows in-cell detection of PPIs in mammalian cells. To enable high-throughput (HT) Protein Interaction Network (PIN) screening, a proteome-scale, cell-based array platform was developed. On top, with KISS and Virotrap, novel strategies to detect PPIs in mammalian cells were developed.
With the MAPPIT-based HT screening platform now being fully operational, a first intracellular PIN focused on vesicular trafficking and cytokine routing was constructed. In the next phase, we will take full advantage of our strategic choice to develop PPI technologies that operate in intact human cells. Indeed, by working in mammalian cells, investigating dynamic interactomics or “dynactomics” by perturbating the cellular or protein context becomes relevant and feasible.
The central, overarching theme of the CYRE ERC advanced grant is cytokine receptor signaling. We seek to gain novel insights in how cytokines activate their cognate receptors and how the resulting signals are modulated to enable optimally tuned cellular and physiological responses. The program aims at advancing both fundamental and applied medical sciences, since many human pathologies, including cancer and auto-immune diseases, are linked to dysfunctional cytokine signaling.

Our approaches are based on several in-house developed novel technologies that allow studying both extra- and intracellular aspects of cytokine receptor functioning. Key objectives include (i) development of AcTakines, a novel class of cell-targeted immunocytokines, (ii) elucidating alternative receptor activation mechanisms using the leptin receptor as a model, (iii) building (dynamic) intracellular signaling interactome maps using optimized MAPPIT/KISS and Virotrap toolboxes.

Reported by

VIB
Belgium
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