Biology of Cytokines & Therapeutic Applications.
Biology of IL-15
IL-15 delivers its signal through the IL-2Rβ/γc dimeric receptor. The private IL-15Rα chain can be expressed together with IL-2Rβ and γc on a same cell forming a high affinity heterotrimeric receptor for IL-15 acting in cis: IL-15 cis-presentation. IL-15Rα can also be brought by a neighboring cell presenting IL-15 in trans to cells expressing the IL-2Rβ/γc dimeric receptor. The later mechanism is called IL-15 trans-presentation.
In the lab, we are interested in depicting precisely the interfaces between IL-15 and each of its three receptor chains: IL-15Rα, IL-2Rβ and γc. For that purpose, we are combining in silico studies with biological observations. These studies are leading us to better understand how IL-15 could act both in cis and in trans.
Role of IL-15Rα shedding during IL-15 trans-presentation. Confocal microscopy analysis of intracellular IL-15 expression within Kit225 responding cells following 1-h coculture with wt.ILR, uncleavable.ILR, or wt.IL-15RαHEK-293 cells. Cells were stained with an Alexa-647–conjugated anti-CD4 Ab, fixed, permeablilized and stained with a FITC–conjugated anti–IL-15 Ab. Each picture is divided in four quadrants: UL shows Z-project XY view; orthogonal views are shown on UR (YZ plane) and LL (XZ plane); and surface plot of XY view on LR (peak = pixel IF). Arrows show IL-15 clusters within Kit225. The two right panels show pictures from a 3D reconstitution. (ILR: membrane-boundIL-15/IL-15Rα complex) (We thank Dr. Steven Nedellec from MicroPicell Platform, SFR Nantes, for technical assistance)
NK and CD8 T cells homeostasis
IL-15 supports the development of various effector cells, including NK and CD8 T cells. In the lab, we are studying the impact of administrating IL-15 on the generation of CD8 and NK populations.
NK and CD8 T cell expansions in response to IL-15/IL-15Ra complexes. Experimental design: One cycle of stimulation with IL-15cplx (D0 and D2) was administered to C57BL/6 mice. The untreated group was injected with PBS. Mice were analyzed at D4.
Selected publications:
- Quéméner A., et al., (2019) J. Cell. Sci. 133(5):jcs236802.
- Frutoso M., et al., (2018) J. Immunol. 201:493.
- Meghnem D., et al., (2017) J. Immunol.198:4563.
- Tamzalit F., et al., (2014) Proc. Natl. Acad. Sci. U S A. 111:8565.
- Mortier E., et al., (2006) J. Biol. Chem. 281:1612.
- Mortier E., et al., (2009) Immunity. 31:811.
- Mortier E., et al., (2008) J. Exp. Med., 205:1213.
- Mortier E., et al., (2004) J. Immunol. 173:1681.
Development of IL-15 derived reagents for therapy
Boosting the immune system for fighting Cancer
Interleukin-15 (IL-15) is a cytokine belonging to the γc family, acting on the proliferation, survival, activation and cytotoxicity of effector immune cells (mainly NK, NK–T, CD8 T cells and memory CD8 T cells). It therefore represents a major cytokine in anti-tumor immune surveillance. We have generated a fusion protein between a portion of IL-15Rα receptor chain and IL-15 itself, capable of mimicking the IL-15 trans-presentation. We are currently testing the therapeutic efficiency of IL-15 in diverses cancer models.
Effect of RLI and IL-15 in a mouse melanoma model. Left. RLI fusion molecule consisting on a portion of IL-15Rα receptor chain (in green) fused to IL-15 (in yellow). Right. RLI or IL-15 was administered i.p. on days 1, 2, and 10. Number of lung metastasis was counted on day 21. Columns, mean of each group. (Dunnett's multiple comparison test).
Effect of anti-CD20-RLI on survival of tumor-bearing SCID mice. Mice were inoculated intravenously with Raji cells (CD20 positive cells). At days 5, 10, 15 and 20 after tumor inoculation, groups of 10 mice were treated with equimolar dose of saline (▽), RLI (large-black-square) , RTX (○), RTX + RLI (black-circle), anti-CD20-RLI (large-white-square) or anti-GD2-RLI (◇).
Selected Publications:
- Fiore P.F., et al., (2020) J. Immunother. Cancer. 8(2):e001428.
- Frutoso M., et al., (2018) J. Immunol. 201:493.
- Vincent M., et al., (2014) mAbs. 6:1026.
- Vincent M., et al., (2013) Int. J. Cancer. 133:757.
- Bessard A., et al., (2009) Mol. Cancer Ther. 8:2736.
- Huntington, N. D., et al., (2009) J. Exp. Med., 206:25.
- Patent: WO2007046006A3
Antagonize IL-15 action to reduce Inflammation.
Uncontrolled IL-15 expression could participate in the induction of autoimmunity. Despite regulatory controls, elevated IL-15 levels have been reported in several autoimmune diseases, including psoriasis, rheumatoid arthritis, lupus, sarcoidosis, celiac disease, and inflammatory bowel disease. Thus, cytokine-mediated inflammation has been translated into the development of novel therapeutic agents. In the lab, we are searching for biological and/or chemical compounds in order to thwart IL-15 overexposure deleterious consequences.
Impeding IL-15's binding to IL-15Ra by NANTIL-15 reduce the signs of inflammation. Collagen induced arthritis model. Clinical score and histology.
Selected Publications:
- Quéméner A., et al., (2017) J. Med. Chem. 60:6249.
- Meghnem D., et al., (2017) J. Immunol. 198:4563.
- Patent: US20180258174
- Patent: US20160130318
- Mortier E., et al. (2020), Front. Immunol., 11:1.