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Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells

Pearson, Frances E., Tullett, Kirsteen M., Leal-Rojas, Ingrid M., Haigh, Oscar L., Masterman, Kelly-Anne, Walpole, Carina, Bridgeman, John S., McLaren, James E., Ladell, Kristin, Miners, Kelly, Llewellyn-Lacey, Sian, Price, David A., Tunger, Antje, Schmitz, Marc, Miles, John J, Lahoud, Mireille H and Radford, Kristen J 2020. Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141+ dendritic cells to activate naïve and memory WT1‐specific CD8+ T cells. Clinical and Translational Immunology 9 10.1002/cti2.1141

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Nature
ISSN: 2050-0068
Date of First Compliant Deposit: 16 July 2020
Date of Acceptance: 4 May 2020
Last Modified: 06 Oct 2020 11:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/133509

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