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IL-21-Mediated Potentiation of Antitumor Cytolytic and Proinflammatory Responses of Human V9V2 T Cells for Adoptive Immunotherapy¹

Aurélie Thedrez^*, Christelle Harly^*, Alexis Morice^*, Samuel Salot, Marc Bonneville^2,* and Emmanuel Scotet^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 892, Centre de Recherche en Cancérologie Nantes-Angers, Nantes, France, and Innate Pharma, Marseille, France

V9V2 T lymphocytes are a major human T cell subset that react against a wide array of tumor cells, through recognition of phosphorylated isoprenoid pathway metabolites called phosphoantigens. Immunotherapeutic protocols targeting V9V2 T cells have yielded promising, yet limited, signs of antitumor efficacy. To improve these approaches, we analyzed the effects on T cells of IL-21, a cytokine known to enhance proliferation and effector functions of CD8⁺ T cells and NK cells. IL-21 induced limited division of phosphoantigen-stimulated V9V2 T cells, but did not modulate their sustained expansion induced by exogenous IL-2. V9V2 T cells expanded in the presence of IL-21 and IL-2 showed enhanced antitumor cytolytic responses, associated with increased expression of CD56 and several lytic molecules, and increased tumor-induced degranulation capacity. IL-21 plus IL-2-expanded V9V2 T cells expressed higher levels of inhibitory receptors (e.g., ILT2 and NKG2A) and lower levels of the costimulatory molecule NKG2D. Importantly, these changes were rapidly and reversibly induced after short-term culture with IL-21. Finally, IL-21 irreversibly enhanced the proinflammatory Th1 polarization of expanded V9V2 T cells when added at the beginning of the culture. These data suggest a new role played by IL-21 in the cytotoxic and Th1 programming of precommitted Ag-stimulated T cells. On a more applied standpoint, IL-21 could be combined to IL-2 to enhance T cell-mediated antitumor responses, and thus represents a promising way to optimize immunotherapies targeting this cell subset.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by institutional grants from Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche Grants A05118GS and PRIB/017, Association pour la Recherche sur le Cancer Grants 3662 and 4953, Institut National du Cancer Grant PLA074, and from the Commission of the European Union Program Cancer Immunotherapy Grants E06005NP/EEA06004GNP.

² Address correspondence and reprint requests to Dr. Emmanuel Scotet or Dr. Marc Bonneville, Institut National de la Santé et de la Recherche Médicale, Unité 892, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Biologie, Centre Hospitalier de l’Université, 9 quai moncousu, 44035 Nantes Cedex, France. E-mail addresses: Emmanuel.Scotet{at}inserm.fr or bonnevil{at}inserm.fr

³ The online version of this article contains supplemental material.

⁴ Abbreviation used in this paper: β₂m, β₂-microglobulin.