BIOLOGY OF IL-15 & THERAPEUTIC APPLICATIONS
Antigen specific memory CD8+ T cells and NK cells are cytolytic lymphocytes that kill infected host and transformed cells. By enhancing their expansion and effector functions, IL-15 is a major cytokine involved in increasing anti-tumor immune responses and the efficacy of vaccines. Both IL-15 and its high affinity receptor, IL-15Rα, are required for IL-15 signaling in vivo. While IL-2 and IL-15 share receptor subunits and some in vitro activities, they display different functions in vivo, IL-2 now appearing to selectively promote the expansion of regulatory T cells, and IL-15 to expand NK cells and rescue memory CD8+ T cells. Indeed, therapeutic trials have recently begun to take advantage of IL-15’s unique immuno-modulatory properties.
IL-15 shares with IL-2 the heterodimeric IL-15Rβ (CD122)/IL-15Rγ (CD132) receptor. Its specificity of action is conferred by its alpha chain, IL-15Rα (CD125). The high affinity of IL-15 for IL-15Rα allows IL-15 to act in trans-presentation: membrane-bound IL-15. IL-15Rα complex interacts and delivers IL-15 signal to cells expressing the CD122/CD132 receptor. Trans-presentation has been shown to be the dominant mechanism delivering IL-15 signal in vivo. Whereas IL-15 mRNA is expressed by a large number of tissues, detection of IL-15 protein is largely limited to monocytes and dendritic cells. This tight regulation is likely required owing to IL-15’s potent pro-inflammatory role. Indeed, IL-15 has been hypothesized to sit at the apex of a pro-inflammatory cytokine cascade which uncontrolled expression would result in the induction of inflammation and autoimmunity.
Deficiencies in IL-15/IL-15Rα signaling compromise the survival and function of CD8+ T cells and NK cells. On the other hand, excess IL-15/IL-15Rα signaling leads to marked expansions of the numbers of these cells and promotes leukemia. Thus, proper regulation of IL-15/IL-15Rα signaling to lymphocytes is critical for both optimal cytolytic immune responses as well as for preventing lymphoid malignancies. Improving our understanding of the regulation of IL-15/IL-15Rα signals and the mechanism(s) by which IL-15 and IL-15Rα support NK cells and memory CD8+ T cells should allow to optimize immune interventions in selected diseases (inflammation, autoimmunity, cancer) as well as treat certain types of leukemia and lymphoma.
Our research team is focused on deciphering IL-15 underpinning molecular mechanisms of regulation, and on determining whether altered expression of IL-15 could underlie aberrant cell activation in the context of inflammation and cancer. Thus, IL-15 represents an interesting pharmacological and therapeutic target in the treatment of certain cancers and inflammatory diseases. Based on different observations depicting IL-15 interaction with its different receptor chains, we have generated, in the laboratory, original IL-15-derived molecules presenting either agonistic or antagonistic activity. We are currently evaluating their potent activity in different models of cancer and inflammation. Our goal is to capitalize on our specificity to strengthen the link between basic understanding of molecular mechanisms and in vivo transfer of original and innovative IL-15-derived drugs.
Erwan Mortier, CR CNRS
Agnès Quéméner, IR1 INSERM
Mike Maillasson, IE2 INSERM
Isabelle Barbieux, AI INSERM
Rui Sousa, PhD Student
Jimmy Smadja, PhD Student
Yannick Jacques, DR CNRS Emeritat
Frutoso M, Morisseau S, Tamzalit F, Quéméner A, Meghnem D, Leray I, Jacques Y, Mortier E. Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles. J Immunol. 2018 Jul 15;201(2):493-506.
Quéméner A, Maillasson M, Arzel L, Sicard B, Vomiandry R, Mortier E, Dubreuil D, Jacques Y, Lebreton J, Mathé-Allainmat M. Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization. J Med Chem. 2017 Jul 27;60(14):6249-6272.
Meghnem D, Morisseau S, Frutoso M, Trillet K, Maillasson M, Barbieux I, Khaddage S, Leray I, Hildinger M, Quéméner A, Jacques Y, Mortier E. Cutting Edge: Differential Fine-Tuning of IL-2- and IL-15-Dependent Functions by Targeting Their Common IL-2/15Rβ/γc Receptor. J Immunol. 2017 Jun 15;198(12):4563-4568.
Jacques Y, Mortier E. [Interleukin 2 revival: a revisited model and new therapeutic applications]. Med Sci (Paris). 2016 Jun-Jul;32(6-7):612-8.
Desbois M, Le Vu P, Coutzac C, Marcheteau E, Béal C, Terme M, Gey A, Morisseau S, Teppaz G, Boselli L, Jacques Y, Béchard D, Tartour E, Cassard L, Chaput N. IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists. J Immunol. 2016 Jul 1;197(1):168-78.
Mortier E, Tamzalit F, Jacques Y, Morisseau S. [Cut the cord, you’re ready to set off on your own!]. Med Sci (Paris). 2014 Oct;30(10):836-8.
Vincent M, Teppaz G, Lajoie L, Solé V, Bessard A, Maillasson M, Loisel S, Béchard D, Clémenceau B, Thibault G, Garrigue-Antar L, Jacques Y, Quéméner A. Highly potent anti-CD20-RLI immunocytokine targeting established human B lymphoma in SCID mouse. MAbs. 2014 Jul-Aug;6(4):1026-37.
Tamzalit F, Barbieux I, Plet A, Heim J, Nedellec S, Morisseau S, Jacques Y, Mortier E. IL-15.IL-15Rα complex shedding following trans-presentation is essential for the survival of IL-15 responding NK and T cells. Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8565-70.
Vincent M, Quéméner A, Jacques Y. Antitumor activity of an immunocytokine composed of an anti-GD2 antibody and the IL-15 superagonist RLI. Oncoimmunology. 2013 Nov 1;2(11):e26441.
Romero AI, Chaput N, Poirier-Colame V, Rusakiewicz S, Jacquelot N, Chaba K, Mortier E, Jacques Y, Caillat-Zucman S, Flament C, Caignard A, Messaoudene M, Aupérin A, Vielh P, Dessen P, Porta C, Mateus C, Ayyoub M, Valmori D, Eggermont A, Robert C, Zitvogel L. Regulation of CD4(+)NKG2D(+) Th1 cells in patients with metastatic melanoma treated with sorafenib: role of IL-15Rα and NKG2D triggering. Cancer Res. 2014 Jan 1;74(1):68-80.
Vincent M, Bessard A, Cochonneau D, Teppaz G, Solé V, Maillasson M, Birklé S, Garrigue-Antar L, Quéméner A, Jacques Y. Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency. Int J Cancer. 2013 Aug 1;133(3):757-65PubMed PMID: 23354868.
Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Plet A, Weijer K, Jacques Y, Spits H, Di Santo JP. Autonomous and extrinsic regulation of thymopoiesis in human immune system (HIS) mice. Eur J Immunol. 2011 Oct;41(10):2883-93.
Pacheco Y, Solé V, Billaud E, Allavena C, Plet A, Ferré V, Garrigue-Antar L, Raffi F, Jacques Y, McIlroy D. Despite an impaired response to IL-7, CD4+EM T cells from HIV-positive patients proliferate normally in response to IL-15 and its superagonist, RLI. AIDS. 2011 Sep 10;25(14):1701-10.
Huntington ND, Alves NL, Legrand N, Lim A, Strick-Marchand H, Mention JJ, Plet A, Weijer K, Jacques Y, Becker PD, Guzman C, Soussan P, Kremsdorf D, Spits H, Di Santo JP. IL-15 transpresentation promotes both human T-cell reconstitution and T-cell-dependent antibody responses in vivo. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6217-22.
Béhar G, Solé V, Defontaine A, Maillasson M, Quéméner A, Jacques Y, Tellier C. Evolution of interleukin-15 for higher E. coli expression and solubility. Protein Eng Des Sel. 2011 Mar;24(3):283-90.
Perdreau H, Mortier E, Bouchaud G, Solé V, Boublik Y, Plet A, Jacques Y. Different dynamics of IL-15R activation following IL-15 cis- or trans-presentation. Eur Cytokine Netw. 2010 Dec;21(4):297-307.
Bouchaud G, Mortier E, Flamant M, Barbieux I, Plet A, Galmiche JP, Jacques Y, Bourreille A. Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn’s disease. Gastroenterology. 2010 Jun;138(7):2378-87.
Bessard A, Solé V, Bouchaud G, Quéméner A, Jacques Y. High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and colorectal cancer. Mol Cancer Ther. 2009 Sep;8(9):2736-45.
Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009 Jan 16;206(1):25-34.
Bouchaud G, Garrigue-Antar L, Solé V, Quéméner A, Boublik Y, Mortier E, Perdreau H, Jacques Y, Plet A. The exon-3-encoded domain of IL-15ralpha contributes to IL-15 high-affinity binding and is crucial for the IL-15 antagonistic effect of soluble IL-15Ralpha. J Mol Biol. 2008 Sep 26;382(1):1-12.
Badoual C, Bouchaud G, Agueznay Nel H, Mortier E, Hans S, Gey A, Fernani F, Peyrard S, -Puig PL, Bruneval P, Sastre X, Plet A, Garrigue-Antar L, Quintin-Colonna F, Fridman WH, Brasnu D, Jacques Y, Tartour E. The soluble alpha chain of interleukin-15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res. 2008 May 15;68(10):3907-14.
Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol. 2007 Dec;8(12):1337-44.
Quéméner A, Bernard J, Mortier E, Plet A, Jacques Y, Tran V. Docking of human interleukin-15 to its specific receptor alpha chain: correlation between molecular modeling and mutagenesis experimental data. Proteins. 2006 Nov 15;65(3):623-36.
Lorenzen I, Dingley AJ, Jacques Y, Grötzinger J. The structure of the interleukin-15 alpha receptor and its implications for ligand binding. J Biol Chem. 2006 Mar 10;281(10):6642-7.
Mortier E, Quéméner A, Vusio P, Lorenzen I, Boublik Y, Grötzinger J, Plet A, Jacques Y. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. J Biol Chem. 2006 Jan 20;281(3):1612-9.
Mortier E, Bernard J, Plet A, Jacques Y. Natural, proteolytic release of a soluble form of human IL-15 receptor alpha-chain that behaves as a specific, high affinity IL-15 antagonist. J Immunol. 2004 Aug 1;173(3):1681-8.
Bernard J, Harb C, Mortier E, Quéméner A, Meloen RH, Vermot-Desroches C, Wijdeness J, van Dijken P, Grötzinger J, Slootstra JW, Plet A, Jacques Y. Identification of an interleukin-15alpha receptor-binding site on human interleukin-15. J Biol Chem. 2004 Jun 4;279(23):24313-22.
Leroy S, Dubois S, Tenaud I, Chebassier N, Godard A, Jacques Y, Dréno B. Interleukin-15 expression in cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). Br J Dermatol. 2001 May;144(5):1016-23.
Lehours P, Raher S, Dubois S, Guo J, Godard A, Jacques Y. Subunit structure of the high and low affinity human interleukin-15 receptors. Eur Cytokine Netw. 2000Jun;11(2):207-15.
Dubois S, Magrangeas F, Lehours P, Raher S, Bernard J, Boisteau O, Leroy S, Minvielle S, Godard A, Jacques Y. Natural splicing of exon 2 of human interleukin-15 receptor alpha-chain mRNA results in a shortened form with a distinct pattern of expression. J Biol Chem. 1999 Sep 17;274(38):26978-84.