Dataset Information

Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141⁺ dendritic cells to activate naive 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 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.

SUBMITTER: Pearson FE

PROVIDER: S-EPMC7292901 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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 FE Tullett Kirsteen M KM Leal-Rojas Ingrid M IM Haigh Oscar L OL Masterman Kelly-Anne KA Walpole Carina C Bridgeman John S JS McLaren James E JE Ladell Kristin K Miners Kelly K Llewellyn-Lacey Sian S Price David A DA Tunger Antje A Schmitz Marc M Miles John J JJ Lahoud Mireille H MH Radford Kristen J KJ

Clinical & translational immunology 20200612 6

<h4>Objectives</h4>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 ...[more]

PMID: 32547743

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Project description:Dendritic 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.

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Dataset Information

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

Objectives

Methods

Results

Conclusions

Publications

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.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Objectives

Methods

Results

Conclusions

Publications

Human CLEC9A antibodies deliver Wilms' tumor 1 (WT1) antigen to CD141&lt;sup&gt;+&lt;/sup&gt; dendritic cells to activate naïve and memory WT1-specific CD8&lt;sup&gt;+&lt;/sup&gt; T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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

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.