Cytokine therapy reverses NK cell anergy in MHC-deficient tumors

Abstract

fit of the cytokine treatment in mice with RMA-S tumors was completely abrogated if the mice were NK-depleted, demonstrating that the effect of the cytokines depended on NK cells ( Figure 1C).The efficacy of cytokine treatments in mice bearing RMA-S tumors did not apply to mice bearing RMA tumors, which are similar to RMA-S cells except that they express high amounts of MHC class I and are therefore resistant to NK cells ( Figure 1B, bottom panel). The survival time in mice with RMA tumors did not change when the mice were treated with cytokines, and was similarly rapid to that in untreated mice with RMA-S tumors.Recently, Levin and colleagues described the "superkine" H9, an engineered version of IL-2, which functions independently of the α chain (CD25) of the IL-2 receptor. Compared with WT IL-2, H9 exhibits much more activity on NK cells and T cells. In vivo, H9 stimulated rejection of B16F10 melanoma tumors in B6 mice (13), but the role of NK cells in rejection has not been investigated. We tested whether H9 induces NK-dependent rejection of MHC class I-deficient tumors by implanting high doses of RMA-S or RMA cells and initiating H9 treatment after 7 days. Similar to the results with IL-12+IL-18 treatment, H9 resulted in improved survival of RMA-S-bearing mice, but had no effect in RMA-bearing mice (Figure 2, A and B). Notably, when mice were depleted of NK cells, the efficacy of H9 treatment was abolished (Figure 2A). These results show that H9 exerts its antitumor effect against MHC class I-deficient tumor cells in an NK cell-dependent fash-

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

“…Especially during the early phase of stem cell or NK cell infusion therapy in which retuning and antileukemic effects occur in parallel, small differences in conditioning regimen, T-cell depletion, or immunosuppression may influence the activation threshold of educated donor NK cells. It would thus be important to prevent adaptation of NK cells to reduced inhibitory input, or to combine the therapy with another NK cell-activating regimen, such as cytokines or ADCC-inducing antibodies (8,9,48).…”

Natural killer cell memory in infection, inflammation and cancer

“…Based on the concepts of cytokine-induced NK memory cells, a Phase I clinical trial using IL-12, IL-15 and IL-18-pre-activated NK cells for treatment of patients with AML recently opened at Washington University School of Medicine, St Louis, Missouri, USA (NCT01898793). The intratumoural application of the cytokines IL-12 and IL-18 was also shown to revert dysfunction of NK cells in the tumour bed of MHC class I-deficient tumour cells 76 . Whether NK cells with a sustained ability for long-term effector function were generated in these studies has not been evaluated.…”

NK cells and cancer: you can teach innate cells new tricks

“…These pre-activated NK cells had better effector functions in vitro, as well as enhanced proliferation, tumour infiltration and tumour control in vivo when tested in mouse models of lymphoma and melanoma 134,135 . Furthermore, recent work by Ardolino et al 136,137 showed that treatment with these cytokines in vivo reversed the tumour-induced anergic state of NK Several challenges must be overcome to optimize the use of NK cells in cancer therapy, including blocking the inhibitory receptors that dampen NK cell activation (FIG. 3a), eliminating T Reg cells that suppress their function, enabling NK cells to traffic into solid tumours, neutrali zing immunosuppressive cytokines such as TGFβ secreted by the tumour (FIG.…”