Research ArticleImmunotherapy

IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy

Science Translational Medicine  28 Oct 2015:
Vol. 7, Issue 311, pp. 311ra170
DOI: 10.1126/scitranslmed.aac8155

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Immunotherapy: Reduce, reuse, recycle

Interleukin-2 (IL-2) is a growth factor used in the clinic to boost immune cell responses to cancer. The related cytokine IL-15 also expands conventional T cells but, unlike IL-2, does not expand regulatory T cells. Now, Su et al. demonstrate that although IL-15 may be effective in lymphopenic patients, IL-2 therapy may be needed in patients who retain immune cells, where T cells compete for available cytokine. The authors show that IL-2 but not IL-15 can sustain signaling after cytokine withdrawal through its high-affinity receptor subunit IL-2Rα. IL-2Rα forms a cell surface reservoir of IL-2 and also aids in recycling IL-2 back to the cell surface, increasing the efficiency of limited quantities of cytokine.

Abstract

Interleukin-2 (IL-2) is a lymphocyte growth factor that is an important component of many immune-based cancer therapies. The efficacy of IL-2 is thought to be limited by the expansion of T regulatory cells, which express the high-affinity IL-2 receptor subunit IL-2Rα. IL-15 is under investigation as an alternative to IL-2. Although both cytokines signal through IL-2Rβγ, IL-15 does not bind IL-2Rα and therefore induces less T regulatory cell expansion. However, we found that transferred effector CD8+ T cells induced curative responses in lymphoreplete mice only with IL-2–based therapy. Although conventional in vitro assays showed similar effector T cell responsiveness to IL-2 and IL-15, upon removal of free cytokine, IL-2 mediated sustained signaling dependent on IL-2Rα. Mechanistically, IL-2Rα sustained signaling by promoting a cell surface IL-2 reservoir and recycling of IL-2 back to the cell surface. Our results demonstrate that IL-2Rα endows T cells with the ability to compete temporally for limited IL-2 via mechanisms beyond ligand affinity. These results suggest that strategies to enhance IL-2Rα expression on tumor-reactive lymphocytes may facilitate the development of more effective IL-2–based therapies.

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