Emergence of NK Cell Hyporesponsiveness after Two IL-15 Stimulation Cycles

Abstract

IL-15 is a cytokine playing a crucial role in the function of immune cells, including NK and CD8 T cells. In this study, we demonstrated that in vivo, in mice, IL-15-prestimulated NK cells were no longer able to respond to a second cycle of IL-15 stimulation. This was illustrated by defects in cell maturation, proliferation, and activation, seemingly linked to the environment surrounding NK cells but not related to the presence of CD4 regulatory T cells, TGF-β, or IL-10. Moreover, NK cells from immunodeficient mice could respond to two cycles of IL-15 stimulation, whereas an adoptive transfer of CD44CD8 cells impaired their responsiveness to the second cycle. Conversely, in immunocompetent mice, NK cell responsiveness to a second IL-15 stimulation was restored by the depletion of CD8 cells. These biological findings refine our understanding of the complex mode of action of NK cells in vivo, and they should be taken into consideration for IL-15-based therapy.

Interleukin-15 and cancer: some solved and many unsolved questions

“…98 Moreover, two recent studies also show that repeated cycles of N-803 injection may lead to reduced biological responsiveness in NK cells of SIV + macaque 99 and, in a phase 1b trial, in patients with metastatic non-small cell lung cancer. 100 These data open up two questions: NK hyporesponsiveness observed in cancer patients receiving repeated cycles of IL-15 or soluble complex is induced by the contemporary expansion of an inhibitory T cell subset as reported in mice 84 or may be directly induced by IL-15 and/or the super-agonist complex? If the second hypothesis holds true, ex vivo protocols for the expansion of NK cells intended to be reinjected in patients with cancer as a complementary immunologic treatment should be Open access solves the above mentioned problems (unpublished results).…”

“…These data highlights as an excessive stimulation of NK cells by sIL-15 and sIL-15/IL-15Rα complexes may induce NK hyporesponsiveness. 84 Indeed, prolonged NK cell activation using ionomycin as well as repeated exposure to Toll-like receptors (TLRs) agonists and 85 repeated injections of interferon (IFN)-α 86 induced decreased cytolytic function and cytokine production. 87 Both TLRs and IFN-α stimulation increase production of IL-15, IL-15Rα and/or of the soluble complex 36 85 86 88 89 that are potentially responsible of NK cells exhaustion.…”

NK Cell Hyporesponsiveness: More Is Not Always Better

“…Since the 1980′s, impact of treatments with IFNα, IL-2, IL-12 or IL-15, on NK cells have been examined in mice. Unexpectedly, while a single treatment with one of the above-mentioned cytokines leads to an increased NK cell cytotoxic activity, multiple treatments with one cytokine was shown to be negatively correlated with NK cell cytotoxic activity [142,143,144,145,146,147,148]. This NK cell hyporesponsiveness driven by cytokines was shown to be systemic [144,148], indicating that the origin of this phenomenon was not linked to a redistribution to other organs.…”

“…However, similar to IL-15, repeated treatments with IL-15 agonists lead to NK cell hyporesponsiveness. This NK cell hyporesponsiveness following multiple treatments is systemic and characterized by impaired activation (altered balance of activating and inhibitory receptors, decreased expression of the CD69 early activation marker), reduced proliferation (decreased Ki67 expression, decreased Stat5 phosphorylation), and decreased anti-tumor activity (decreased clearance of B16F10 tumor cells in a metastatic model) [146,148]. Importantly, NK cell hyporesponsiveness following repeated treatment with IL-2, IL-15 or IL-15 agonists was not linked to a decreased expression of the CD122 CD132 chains [144,146,148] indicating that NK cells should be able to respond to the cytokines when re-injected (Figure 3).…”

“…In mice, one study hypothesized the implication of regulatory cells or immunosuppressive cytokines but lacked sufficient evidence [144]. Moreover, regulatory T cells, immunosuppressive cytokines such as IL-10 or TGFβ, and also IFNγ, were shown not to be involved in IL-15 repeated treatment [146,148]. Studies from Saito and colleagues in 1985 have shown that NK cell hyporesponsiveness following repeated treatment with cytokine was linked to a decreased percentage of large granular lymphocytes (LGL), the effector cell population responsible for NK cell-mediated cytotoxicity [142,143].…”