title: Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice.
abstract: A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-gamma production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and CD8(+) T cells.
authors.affiliation: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Lou
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
authors.forename: Hong
authors.initials: H
authors.lastname: Qin
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.forename: Grace J
authors.initials: GJ
authors.lastname: Kim
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000502:physiology; D053262:Receptors, OX40 / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D016207:Cytokines; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D009838:Oligodeoxyribonucleotides; D019713:Receptors, CCR5; D053262:Receptors, OX40; C495370:Tlr9 protein, mouse; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D051217:Toll-Like Receptor 9; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma