Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells
Abstract Objectives Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed ex...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Clinical & Translational Immunology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cti2.1141 |
| _version_ | 1818308545388478464 |
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| author | Frances E Pearson Kirsteen M Tullett Ingrid M Leal‐Rojas Oscar L Haigh Kelly‐Anne Masterman Carina Walpole John S Bridgeman James E McLaren Kristin Ladell Kelly Miners Sian Llewellyn‐Lacey David A Price Antje Tunger Marc Schmitz John J Miles Mireille H Lahoud Kristen J Radford |
| author_facet | Frances E Pearson Kirsteen M Tullett Ingrid M Leal‐Rojas Oscar L Haigh Kelly‐Anne Masterman Carina Walpole John S Bridgeman James E McLaren Kristin Ladell Kelly Miners Sian Llewellyn‐Lacey David A Price Antje Tunger Marc Schmitz John J Miles Mireille H Lahoud Kristen J Radford |
| author_sort | Frances E Pearson |
| collection | DOAJ |
| description | Abstract Objectives Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1. |
| first_indexed | 2024-12-13T07:15:59Z |
| format | Article |
| id | doaj.art-d7716a6649ca41f9a6290ec9da9eae79 |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-12-13T07:15:59Z |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-d7716a6649ca41f9a6290ec9da9eae792022-12-21T23:55:34ZengWileyClinical & Translational Immunology2050-00682020-01-0196n/an/a10.1002/cti2.1141Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cellsFrances E Pearson0Kirsteen M Tullett1Ingrid M Leal‐Rojas2Oscar L Haigh3Kelly‐Anne Masterman4Carina Walpole5John S Bridgeman6James E McLaren7Kristin Ladell8Kelly Miners9Sian Llewellyn‐Lacey10David A Price11Antje Tunger12Marc Schmitz13John J Miles14Mireille H Lahoud15Kristen J Radford16Cancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaInfection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaCancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaCancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaCancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaCancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKDivision of Infection and Immunity Cardiff University School of Medicine Cardiff UKInstitute of Immunology Faculty of Medicine Carl Gustav Carus Technische Universistät Dresden Dresden GermanyInstitute of Immunology Faculty of Medicine Carl Gustav Carus Technische Universistät Dresden Dresden GermanyAustralian Institute of Health and Medical Research James Cook University Cairns QLD AustraliaInfection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton VIC AustraliaCancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 AustraliaAbstract Objectives Vaccines that prime Wilms' tumor 1 (WT1)‐specific CD8+ T cells are attractive cancer immunotherapies. However, immunogenicity and clinical response rates may be enhanced by delivering WT1 to CD141+ dendritic cells (DCs). The C‐type lectin‐like receptor CLEC9A is expressed exclusively by CD141+ DCs and regulates CD8+ T‐cell responses. We developed a new vaccine comprising a human anti‐CLEC9A antibody fused to WT1 and investigated its capacity to target human CD141+ DCs and activate naïve and memory WT1‐specific CD8+ T cells. Methods WT1 was genetically fused to antibodies specific for human CLEC9A, DEC‐205 or β‐galactosidase (untargeted control). Activation of WT1‐specific CD8+ T‐cell lines following cross‐presentation by CD141+ DCs was quantified by IFNγ ELISPOT. Humanised mice reconstituted with human immune cell subsets, including a repertoire of naïve WT1‐specific CD8+ T cells, were used to investigate naïve WT1‐specific CD8+ T‐cell priming. Results The CLEC9A‐WT1 vaccine promoted cross‐presentation of WT1 epitopes to CD8+ T cells and mediated priming of naïve CD8+ T cells more effectively than the DEC‐205‐WT1 and untargeted control‐WT1 vaccines. Conclusions Delivery of WT1 to CD141+ DCs via CLEC9A stimulates CD8+ T cells more potently than either untargeted delivery or widespread delivery to all Ag‐presenting cells via DEC‐205, suggesting that cross‐presentation by CD141+ DCs is sufficient for effective CD8+ T‐cell priming in humans. The CLEC9A‐WT1 vaccine is a promising candidate immunotherapy for malignancies that express WT1.https://doi.org/10.1002/cti2.1141cancer immunotherapyCD141CLEC9Adendritic cellsvaccinesWilms' tumor 1 |
| spellingShingle | Frances E Pearson Kirsteen M Tullett Ingrid M Leal‐Rojas Oscar L Haigh Kelly‐Anne Masterman Carina Walpole John S Bridgeman James E McLaren Kristin Ladell Kelly Miners Sian Llewellyn‐Lacey David A Price Antje Tunger Marc Schmitz John J Miles Mireille H Lahoud Kristen J Radford Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells Clinical & Translational Immunology cancer immunotherapy CD141 CLEC9A dendritic cells vaccines Wilms' tumor 1 |
| title | Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells |
| title_full | Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells |
| title_fullStr | Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells |
| title_full_unstemmed | Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells |
| title_short | Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells |
| title_sort | human clec9a antibodies deliver wilms tumor 1 wt1 antigen to cd141 dendritic cells to activate naive and memory wt1 specific cd8 t cells |
| topic | cancer immunotherapy CD141 CLEC9A dendritic cells vaccines Wilms' tumor 1 |
| url | https://doi.org/10.1002/cti2.1141 |
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