title: IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.
abstract: To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival.
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Kritikou
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Carin I M
authors.initials: CI
authors.lastname: Dahlberg
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Marisa A P
authors.initials: MA
authors.lastname: Baptista
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Arnika K
authors.initials: AK
authors.lastname: Wagner
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Pinaki P
authors.initials: PP
authors.lastname: Banerjee
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Lavesh Amar
authors.initials: LA
authors.lastname: Gwalani
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Poli
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Sudeepta K
authors.initials: SK
authors.lastname: Panda
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wermeling
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Brauner
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000970:Antineoplastic Agents / Q000378:metabolism*; D019002:CD56 Antigen / Q000032:analysis; D015550:Cell Degranulation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency*; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D000098862:T Lineage-Specific Activation Antigen 1; D019002:CD56 Antigen; D007376:Interleukin-2; C522918:NCAM1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D007371:Interferon-gamma