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Endogenous IL-21 Restricts CD8⁺ T Cell Expansion and Is not Required for Tumor Immunity¹

Henrik Søndergaard,^* Jonathan M. Coquet, Adam P. Uldrich,^* Nicole McLaughlin,^* Dale I. Godfrey, Pallavur V. Sivakumar, Kresten Skak, and Mark J. Smyth^2*

^*Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia; Immunopharmacology, Novo Nordisk A/S, Måløv, Denmark; and Zymogenetics, Seattle, WA 98102

IL-21 has antitumor activity through actions on NK cells and CD8⁺ T cells, and is currently in clinical development for the treatment of cancer. However, no studies have addressed the role of endogenous IL-21 in tumor immunity. In this study, we have studied both primary and secondary immune responses in IL-21^–/– and IL-21R^–/– mice against several experimental tumors. We found intact immune surveillance toward methylcholanthrene-induced sarcomas in IL-21^–/– and IL-21R^–/– mice compared with wild-type mice and B16 melanomas showed equal growth kinetics and development of lung metastases. IL-21R^–/– mice showed competent NK cell-mediated rejection of NKG2D ligand (Rae1β) expressing H-2b^– RMAS lymphomas and sustained transition to CD8⁺ T cell-dependent memory against H-2b⁺ RMA lymphomas. -Galactosylceramide stimulation showed equal expansion and activation of NKT and NK cells and mounted a powerful antitumor response in the absence of IL-21 signaling, despite reduced expression of granzyme B in NKT, NK, and CD8⁺ T cells. Surprisingly, host IL-21 significantly restricted the expansion of Ag-specific CD8⁺ T cells and inhibited primary CD8⁺ T cell immunity against OVA-expressing EG7 lymphomas, as well as the secondary expansion of memory CD8⁺ T cells. However, host IL-21 did not alter the growth of less immunogenic MC38 colon carcinomas with dim OVA expression. Overall, our results show that endogenous IL-21/IL-21R is not required for NK, NKT, and CD8⁺ T cell-mediated tumor immunity, but restricts Ag-specific CD8⁺ T cell expansion and rejection of immunogenic tumors, indicating novel immunosuppressive actions of this cytokine.

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 Grant 454569 from the National Health and Medical Research Council of Australia Program (to M.J.S., and D.I.G.), by a Cancer Research Institute Postgraduate Scholarship (to J.M.C.), a Doherty Fellowship (to A.P.U.), and by National Health and Medical Research Council Research Fellowships (to M.J.S. and D.I.G.). D.I.G. and M.J.S. have received research support from Novo Nordisk A/S.

² Address correspondence and reprint requests to Dr. Mark J. Smyth, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, Victoria, Australia. E-mail address: mark.smyth{at}petermac.org

³ Abbreviations used in this paper: DC, dendritic cell; MCA, methylcholanthrene; GC, alpha-galactosylceramide; MSCV, murine stem cell virus; WT, wild type.