Masterman and Haigh et al. developed a novel human CD141+ dendritic cell (DC)-targeted vaccine consisting of an anti-CLEC9A Ab fused to antigenic epitopes of the cancer testis antigen NY-ESO-1 (CLEC9-NY Ab). Compared to DEC-205-NY, which binds all human DCs, or a non-binding control Ab, CLEC9-NY Ab bound specifically to CD141+ DCs and was superior in delivering and cross-presenting multiple NY epitopes to CD141+ DCs, activating NY-specific CD8+ T cells, and priming naive CD8+ T cells for effector function and lytic activity. In melanoma patient samples, CLEC9-NY Ab reactivated NY-specific memory T cell responses ex vivo.
Contributed by Katherine Turner
BACKGROUND: Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8(+) T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141(+) DCs, the human cDC1 equivalent. CD141(+) DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8(+) T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141(+) DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific nave and memory CD8(+) T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. METHODS: Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8(+) T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon _ (IFN_) production following incubation of CD141(+) DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of nave NY-ESO-1-specific CD8(+) T cells were used to investigate nave T cell priming. T cell effector function was measured by expression of IFN_, MIP-1_, tumor necrosis factor and CD107a and by lysis of target tumor cells. RESULTS: CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141(+) DCs for activation of NY-ESO-1-specific CD8(+) T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of nave NY-ESO-1-specific CD8(+) T cells with polyclonal effector function and potent tumor killing capacity in vitro. CONCLUSIONS: These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141(+) DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.
Author Info: (1) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (2) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Aus
Author Info: (1) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (2) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (3) Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. (4) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (5) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (6) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (7) Department of Hematology and Oncology, Olivia Newton John Cancer Research Institute, Heidelberg, Victoria, Australia. (8) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (9) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (10) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (11) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia. (12) Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. (13) Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA. (14) Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA. (15) Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA. (16) Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. (17) Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia kristen.radford@mater.uq.edu.au.
