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

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. α-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.