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- Title
Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141<sup>+</sup> dendritic cells to activate naïve and memory WT1‐specific CD8<sup>+</sup> T cells.
- Authors
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; Radford, Kristen J
- 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.
- Subjects
NEPHROBLASTOMA; T cells; DENDRITIC cells; IMMUNOGLOBULINS; ANTIGENS; HYPERCOAGULATION disorders
- Publication
Clinical & Translational Immunology, 2020, Vol 9, Issue 6, p1
- ISSN
2050-0068
- Publication type
Article
- DOI
10.1002/cti2.1141