Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/23917
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dc.contributor.authorMasterman, Kelly-Anne-
dc.contributor.authorHaigh, Oscar L-
dc.contributor.authorTullett, Kirsteen M-
dc.contributor.authorLeal-Rojas, Ingrid M-
dc.contributor.authorWalpole, Carina-
dc.contributor.authorPearson, Frances E-
dc.contributor.authorCebon, Jonathan S-
dc.contributor.authorSchmidt, Christopher-
dc.contributor.authorO'Brien, Liam-
dc.contributor.authorRosendahl, Nikita-
dc.contributor.authorDaraj, Ghazal-
dc.contributor.authorCaminschi, Irina-
dc.contributor.authorGschweng, Eric H-
dc.contributor.authorHollis, Roger P-
dc.contributor.authorKohn, Donald B-
dc.contributor.authorLahoud, Mireille H-
dc.contributor.authorRadford, Kristen J-
dc.date2020-07-
dc.date.accessioned2020-08-03T06:35:49Z-
dc.date.available2020-08-03T06:35:49Z-
dc.date.issued2020-07-
dc.identifier.citationJournal for Immunotherapy of Cancer 2020; 8(2): e000691en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/23917-
dc.description.abstractDendritic 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 naïve 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. 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 γ (IFNγ) 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 naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells. 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 naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. 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.en
dc.language.isoeng
dc.subjectdendritic cellsen
dc.subjectimmunogenicity, vaccineen
dc.subjectimmunotherapyen
dc.subjectmelanomaen
dc.titleHuman CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells.en
dc.typeJournal Articleen
dc.identifier.journaltitleJournal for Immunotherapy of Canceren
dc.identifier.affiliationMonash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australiaen
dc.identifier.affiliationDepartment of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USAen
dc.identifier.affiliationOlivia Newton-John Cancer Research Instituteen
dc.identifier.affiliationMater Research Institute, University of Queensland, Woolloongabba, Queensland, Australiaen
dc.identifier.affiliationClinical Haematologyen
dc.identifier.affiliationMedical Oncologyen
dc.identifier.doi10.1136/jitc-2020-000691en
dc.type.contentTexten
dc.identifier.orcid0000-0001-6512-6323en
dc.identifier.pubmedid32737142
dc.type.austinJournal Article
local.name.researcherCebon, Jonathan S
item.openairetypeJournal Article-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en-
crisitem.author.deptOlivia Newton-John Cancer Research Institute-
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