IL2 variant circumvents ICOS+ regulatory T-cell expansion and promotes NK cell activation

Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W. Overwijk, Jason Roszik, Francesco Marincola, Patrick Hwu, Elizabeth Grimm, Laszlo Radvanyi

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11 Citations (Scopus)

Abstract

Clinical responses to high-dose IL2 therapy are limited due to selective expansion of CD4+CD25+Foxp3+ T-regulatory cells (Treg), especially ICOS+ Tregs, rather than natural killer (NK) cells and effector T cells. These ICOS+ Tregs are highly suppressive and constitutively express high levels of IL2Rα (CD25) and CD39. Here, we characterized the effect of a mutant form of IL2 (F42K), which preferentially binds to the lower affinity IL2Rβγ with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets. Unlike wild-type (WT) IL2, F42K did not efficiently induce the expansion of highly suppressive ICOS+ Tregs in peripheral blood mononuclear cells (PBMC) from healthy controls and melanoma patients. Instead, it promoted the expansion of CD16+CD56+ NK cells and CD56hiCD16- NK cell subsets in both short- and long-term cultures, with enhanced Bcl-2 expression. Stimulation of PBMCs with F42K induced expression of more NK cell activation molecules, such as NKp30, NKp44, DNAM-1, NKG2D, 4-1BB/CD137, and Tim-3, than WT IL2. F42K induced greater upregulation of TRAIL, and NK-mediated cytolytic activity was increased against both autologous and HLA-mismatched melanoma cells compared with WT IL2. Gene expression analysis revealed distinct gene expression profiles stimulated by F42K, WT IL2, and IL15. F42K therapy in vivo also induced a dramatic reduction in the expansion of ICOS+ Tregs, promoted NK cell expansion, and inhibited melanoma tumor growth more efficiently than WT IL2 and more effectively than anti-CTLA-4. Our findings suggest that F42K could be a potential substitute for WT IL2 as a cytokine therapy for cancer.

Original languageEnglish
Pages (from-to)983-994
Number of pages12
JournalCancer immunology research
Volume4
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Sim, G. C., Liu, C., Wang, E., Liu, H., Creasy, C., Dai, Z., Overwijk, W. W., Roszik, J., Marincola, F., Hwu, P., Grimm, E., & Radvanyi, L. (2016). IL2 variant circumvents ICOS+ regulatory T-cell expansion and promotes NK cell activation. Cancer immunology research, 4(11), 983-994. https://doi.org/10.1158/2326-6066.CIR-15-0195