title: Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells.
abstract: IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10. Enhanced secretion of IFNgamma was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.
authors.affiliation: Laboratory of Experimental Tumour Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. n.pouw@erasmusmc.nl
authors.forename: Nadine
authors.initials: N
authors.lastname: Pouw
authors.forename: Elike
authors.initials: E
authors.lastname: Treffers-Westerlaken
authors.forename: Jaco
authors.initials: J
authors.lastname: Kraan
authors.forename: Floyd
authors.initials: F
authors.lastname: Wittink
authors.forename: Timo
authors.initials: T
authors.lastname: ten Hagen
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D054353:Perforin / Q000096:biosynthesis / Q000235:genetics; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D058951:gp100 Melanoma Antigen; D000098546:Interleukin-21
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D015789:HLA-A2 Antigen; D019409:Interleukin-15; D007378:Interleukins; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D054353:Perforin; D053804:Granzymes; D000098546:Interleukin-21