title: IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists.
abstract: Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity.
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France; INSERM, Centre d'Investigation Clinique Biothérapie 1428, Villejuif F-94805, France; Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre F-94276, France; Cytune Pharma, Nantes F-44300, France;
authors.forename: Mélanie
authors.identifier: 0000-0001-5503-8821
authors.initials: M
authors.lastname: Desbois
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France;
authors.forename: Pauline
authors.identifier: 0000-0002-2788-5019
authors.initials: P
authors.lastname: Le Vu
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France; Université Paris-Sud, Faculté de Médecine, Le Kremlin Bicêtre F-94276, France;
authors.forename: Clélia
authors.identifier: 0000-0001-6528-9907
authors.initials: C
authors.lastname: Coutzac
authors.affiliation: INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris-Descartes, Sorbonne Paris Cité, Paris F-75015, France;
authors.forename: Elie
authors.identifier: 0000-0001-6630-9682
authors.initials: E
authors.lastname: Marcheteau
authors.affiliation: INSERM, Centre d'Investigation Clinique Biothérapie 1428, Villejuif F-94805, France;
authors.forename: Coralie
authors.identifier: 0000-0002-3150-5664
authors.initials: C
authors.lastname: Béal
authors.affiliation: INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris-Descartes, Sorbonne Paris Cité, Paris F-75015, France;
authors.forename: Magali
authors.initials: M
authors.lastname: Terme
authors.affiliation: INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris-Descartes, Sorbonne Paris Cité, Paris F-75015, France;
authors.forename: Alain
authors.initials: A
authors.lastname: Gey
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Institut de Recherche en Santé - Université de Nantes, Nantes F-44093, France; and Centre Hospitalier Universitaire Hôtel Dieu, Nantes F-44093, France.
authors.forename: Sébastien
authors.identifier: 0000-0002-7175-0031
authors.initials: S
authors.lastname: Morisseau
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Institut de Recherche en Santé - Université de Nantes, Nantes F-44093, France; and.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Teppaz
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France;
authors.forename: Lisa
authors.identifier: 0000-0003-0072-2428
authors.initials: L
authors.lastname: Boselli
authors.affiliation: Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Institut de Recherche en Santé - Université de Nantes, Nantes F-44093, France; and.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.affiliation: Cytune Pharma, Nantes F-44300, France;
authors.forename: David
authors.identifier: 0000-0003-1817-3324
authors.initials: D
authors.lastname: Béchard
authors.affiliation: INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris-Descartes, Sorbonne Paris Cité, Paris F-75015, France;
authors.forename: Eric
authors.identifier: 0000-0002-7323-468X
authors.initials: E
authors.lastname: Tartour
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France;
authors.forename: Lydie
authors.identifier: 0000-0001-8373-041X
authors.initials: L
authors.lastname: Cassard
authors.affiliation: Gustave Roussy, Laboratoire d'Immunomonitoring en Oncologie, Villejuif F-94805, France; Centre National de la Recherche Scientifique, Unité Mixte de Service 3655, Villejuif F-94805, France; INSERM, US23, Villejuif, F-94805, France; INSERM, Centre d'Investigation Clinique Biothérapie 1428, Villejuif F-94805, France; nathalie.chaput@gustaveroussy.fr.
authors.forename: Nathalie
authors.identifier: 0000-0003-2506-7853
authors.initials: N
authors.lastname: Chaput
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D019409:Interleukin-15 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C568159:IL-15Ralpha-sushi domain-linker-IL-15 fusion protein; D019409:Interleukin-15; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor