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

John J Miles¹  Kristen J Radford²  Kelly‐Anne Masterman²  Carina Walpole²  Ingrid M Leal‐Rojas²  Oscar L Haigh²  Frances E Pearson²  Kelly Miners³  David A Price³  Kristin Ladell³  John S Bridgeman³  James E McLaren³  Sian Llewellyn‐Lacey³  Kirsteen M Tullett⁴  Mireille H Lahoud⁴  Antje Tunger⁵  Marc Schmitz⁵ 

[1] Australian Institute of Health and Medical Research James Cook University Cairns QLD Australia;Cancer Immunotherapies Laboratory Mater Research Institute — The University of Queensland Translational Research Institute Woolloongabba Australia 4102 Australia;Division of Infection and Immunity Cardiff University School of Medicine Cardiff UK;Infection and Immunity Program Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology Monash University Clayton VIC Australia;Institute of Immunology Faculty of Medicine Carl Gustav Carus Technische Universistät Dresden Dresden Germany;

关键词: cancer immunotherapy;    CD141;    CLEC9A;    dendritic cells;    vaccines;    Wilms' tumor 1;   

DOI  :  10.1002/cti2.1141

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown