title: NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells.
abstract: Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8(+) T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell-depleted mice exhibited a significantly higher frequency of SIY-specific CD8(+) T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8(+) T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell-depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8(+) T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Ximena L Raffo
authors.identifier: 0000-0002-8891-4821
authors.initials: XL
authors.lastname: Iraolagoitia
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Raul G
authors.identifier: 0000-0001-5402-3687
authors.initials: RG
authors.lastname: Spallanzani
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Nicolás I
authors.initials: NI
authors.lastname: Torres
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Romina E
authors.identifier: 0000-0001-9787-2670
authors.initials: RE
authors.lastname: Araya
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Andrea
authors.initials: A
authors.lastname: Ziblat
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Domaica
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Sierra
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Sol Y
authors.identifier: 0000-0002-7856-2973
authors.initials: SY
authors.lastname: Nuñez
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina;
authors.forename: Florencia
authors.initials: F
authors.lastname: Secchiari
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637; Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires C1121ABG, Argentina; and Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
authors.forename: Norberto W
authors.identifier: 0000-0001-7098-359X
authors.initials: NW
authors.lastname: Zwirner
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad de Buenos Aires C1428ADN, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina merfuer@gmail.com.
authors.forename: Mercedes B
authors.identifier: 0000-0002-2734-1468
authors.initials: MB
authors.lastname: Fuertes
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor