2. Academic Validation
  3. Single Domain Antibody-Mediated Blockade of Programmed Death-Ligand 1 on Dendritic Cells Enhances CD8 T-cell Activation and Cytokine Production

Single Domain Antibody-Mediated Blockade of Programmed Death-Ligand 1 on Dendritic Cells Enhances CD8 T-cell Activation and Cytokine Production

  • Vaccines (Basel). 2019 Aug 7;7(3):85. doi: 10.3390/vaccines7030085.
Katrijn Broos 1,  Quentin Lecocq 1,  Brenda De Keersmaecker 1,  Geert Raes 2 3,  Jurgen Corthals 1,  Eva Lion 4 5,  Kris Thielemans 1,  Nick Devoogdt 6,  Marleen Keyaerts 6 7,  Karine Breckpot 8
Affiliations

Affiliations

  • 1 Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium.
  • 2 Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium.
  • 3 Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, 1090 Brussels, Belgium.
  • 4 Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, Faculty of Medicine and Health Sciences, University of Antwerp, 2650 Antwerp, Belgium.
  • 5 Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, 2650 Antwerp, Belgium.
  • 6 In Vivo Cellular and Molecular Imaging Laboratory, VUB, 1090 Brussels, Belgium.
  • 7 Nuclear Medicine Department, UZ Brussel, 1090 Brussels, Belgium.
  • 8 Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium. karine.breckpot@vub.be.
PMID: 31394834 DOI: 10.3390/vaccines7030085
Abstract

Dendritic cell [DC] vaccines can induce durable clinical responses, at least in a fraction of previously treated, late stage Cancer patients. Several preclinical studies suggest that shielding programmed death-ligand 1 [PD-L1] on the DC surface may be an attractive strategy to extend such clinical benefits to a larger patient population. In this study, we evaluated the use of single domain antibody [sdAb] K2, a high affinity, antagonistic, PD-L1 specific sdAb, for its ability to enhance DC mediated T-cell activation and benchmarked it against the use of the monoclonal antibodies [mAbs], MIH1, 29E.2A3 and avelumab. Similar to mAbs, sdAb K2 enhanced antigen-specific T-cell receptor signaling in PD-1 positive (PD-1pos) reporter cells activated by DCs. We further showed that the activation and function of antigen-specific CD8 positive (CD8pos) T cells, activated by DCs, was enhanced by inclusion of sdAb K2, but not mAbs. The failure of mAbs to enhance T-cell activation might be explained by their low efficacy to bind PD-L1 on DCs when compared to binding of PD-L1 on non-immune cells, whereas sdAb K2 shows high binding to PD-L1 on immune as well as non-immune cells. These data provide a rationale for the inclusion of sdAb K2 in DC-based immunotherapy strategies.

Keywords

PD-L1; cancer; dendritic cell; human; immunotherapy; nanobody; single domain antibody; vaccination.

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