title: CLEC12A-Mediated Antigen Uptake and Cross-Presentation by Human Dendritic Cell Subsets Efficiently Boost Tumor-Reactive T Cell Responses.
abstract: Potent immunotherapies are urgently needed to boost antitumor immunity and control disease in cancer patients. As dendritic cells (DCs) are the most powerful APCs, they are an attractive means to reinvigorate T cell responses. An appealing strategy to use the effective Ag processing and presentation machinery, T cell stimulation and cross-talk capacity of natural DC subsets is in vivo tumor Ag delivery. In this context, endocytic C-type lectin receptors are attractive targeting molecules. In this study, we investigated whether CLEC12A efficiently delivers tumor Ags into human DC subsets, facilitating effective induction of CD4(+) and CD8(+) T cell responses. We confirmed that CLEC12A is selectively expressed by myeloid cells, including the myeloid DC subset (mDCs) and the plasmacytoid DC subset (pDCs). Moreover, we demonstrated that these DC subsets efficiently internalize CLEC12A, whereupon it quickly translocates to the early endosomes and subsequently routes to the lysosomes. Notably, CLEC12A Ab targeting did not negatively affect DC maturation or function. Furthermore, CLEC12A-mediated delivery of keyhole limpet hemocyanin resulted in enhanced proliferation and cytokine secretion by keyhole limpet hemocyanin-experienced CD4(+) T cells. Most importantly, CLEC12A-targeted delivery of HA-1 long peptide resulted in efficient Ag cross-presentation by mDCs and pDCs, leading to strong ex vivo activation of HA-1-specific CD8(+) T cells of patients after allogeneic stem cell transplantation. Collectively, these data indicate that CLEC12A is an effective new candidate with great potential for in vivo Ag delivery into mDCs and pDCs, thereby using the specialized functions and cross-talk capacity of these DC subsets to boost tumor-reactive T cell immunity in cancer patients.
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Tim J A
authors: 0000-0002-5353-1740
authors: TJ
authors: Hutten
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Soley
authors: S
authors: Thordardottir
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Hanny
authors: H
authors: Fredrix
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Lisanne
authors: 0000-0001-5097-7272
authors: L
authors: Janssen
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Rob
authors: R
authors: Woestenenk
authors: Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands;
authors: Jurjen
authors: 0000-0002-7213-3422
authors: J
authors: Tel
authors: Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands;
authors: Ben
authors: 0000-0002-7192-4062
authors: B
authors: Joosten
authors: Department of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands;
authors: Alessandra
authors: A
authors: Cambi
authors: Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands;
authors: Mirjam H M
authors: 0000-0001-6320-9133
authors: MH
authors: Heemskerk
authors: Department of Nuclear Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Gerben M
authors: GM
authors: Franssen
authors: Department of Nuclear Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Otto C
authors: 0000-0001-6832-101X
authors: OC
authors: Boerman
authors: Merus N.V., 3584 CH Utrecht, the Netherlands; and.
authors: Lex B H
authors: 0000-0003-4343-3466
authors: LB
authors: Bakker
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Joop H
authors: JH
authors: Jansen
authors: Department of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors: Nicolaas
authors: 0000-0001-7696-4752
authors: N
authors: Schaap
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands;
authors: Harry
authors: H
authors: Dolstra
authors: Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Willemijn.Hobo@Radboudumc.nl.
authors: Willemijn
authors: 0000-0002-8206-8185
authors: W
authors: Hobo
mesh_terms: D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D011975:Receptors, Mitogen / Q000276:immunology*
chemical_list: D000941:Antigens; C485220:CLEC12A protein, human; D037181:Lectins, C-Type; D011975:Receptors, Mitogen