title: IL2 Variant Circumvents ICOS+ Regulatory T-cell Expansion and Promotes NK Cell Activation.
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. Cancer Immunol Res; 4(11); 983-94. ©2016 AACR.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. laszlo.radvanyi@emdserono.com gcsim1@yahoo.co.uk.|Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Geok Choo
authors.initials: GC
authors.lastname: Sim
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Creasy
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marincola
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Grimm
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. laszlo.radvanyi@emdserono.com gcsim1@yahoo.co.uk.|Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003062:Codon; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D019254:Genes, bcl-2; D014644:Genetic Variation; D064593:Heterografts; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D003062:Codon; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2