Long-term cytokine therapy with IL-15/IL-15Rα complexes leads to impaired NK cell function (131.11)

Abstract

Immunotherapies targeting effector lymphocytes are promising approaches for the treatment of cancer and infectious diseases. One such approach employs IL-15/IL-15Rα complexes which are considerably more potent than IL-15 in expanding cytotoxic lymphocytes including NK and CD8 T cells. Recent studies demonstrated that short-term treatment with IL-15/IL-15Rα complexes is highly effective in driving a transient but substantial reduction in tumor burden via immune-mediated mechanisms whereas continuous cytokine therapy improves survival only modestly and fails to control tumor outgrowth. Given the limited efficacy of long-term therapy, we sought to investigate the impact of continuous in vivo stimulation with IL-15/IL-15Rα complexes on NK and CD8 T cells in tumor-free mice. Long-term treatment with IL-15/IL-15Rα complexes triggered massive expansion of NK and CD8 T cells. Strikingly, however, NK cells exhibited marked defects in activation, IFNγ production, degranulation, and cytotoxicity whereas CD8 T cells showed enhanced functional capacity. Additionally, continuous treatment generated a suppressive environment for transferred naïve NK and CD8 T cells and resulted in accumulation of CD11b+Gr1+ cells. The mechanistic basis for NK cell dysfunction upon chronic stimualation with IL-15/IL-15Ra complexes will be discussed. Our results have important clinical implications for the design of immunotherapies and vaccines using multiple doses of immunostimulatory agents.