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Type: Journal article
Title: Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy
Author: Zeng, B.
Middelberg, A.
Gemiarto, A.
MacDonald, K.
Baxter, A.
Talekar, M.
Moi, D.
Tullett, K.
Caminschi, I.
Lahoud, M.
Mazzieri, R.
Dolcetti, R.
Thomas, R.
Citation: Journal of Clinical Investigation, 2018; 128(5):1971-1984
Publisher: American Society for Clinical Investigation
Issue Date: 2018
ISSN: 0021-9738
Abstract: Non–antigen-specific stimulatory cancer immunotherapies are commonly complicated by off-target effects. Antigen-specific immunotherapy, combining viral tumor antigen or personalized neoepitopes with immune targeting, offers a solution. However, the lack of flexible systems targeting tumor antigens to cross-presenting dendritic cells (DCs) limits clinical development. Although antigen–anti-Clec9A mAb conjugates target cross-presenting DCs, adjuvant must be codelivered for cytotoxic T lymphocyte (CTL) induction. We functionalized tailored nanoemulsions encapsulating tumor antigens to target Clec9A (Clec9A-TNE). Clec9A-TNE encapsulating OVA antigen targeted and activated cross-presenting DCs without additional adjuvant, promoting antigen-specific CD4⁺ and CD8⁺ T cell proliferation and CTL and antibody responses. OVA-Clec9A-TNE-induced DC activation required CD4 and CD8 epitopes, CD40, and IFN-α. Clec9A-TNE encapsulating HPV E6/E7 significantly suppressed HPV-associated tumor growth, while E6/E7-CpG did not. Clec9A-TNE loaded with pooled B16-F10 melanoma neoepitopes induced epitope-specific CD4⁺ and CD8⁺ T cell responses, permitting selection of immunogenic neoepitopes. Clec9A-TNE encapsulating 6 neoepitopes significantly suppressed B16-F10 melanoma growth in a CD4⁺ T cell-dependent manner. Thus, cross-presenting DCs targeted with antigen-Clec9A-TNE stimulate therapeutically effective tumor-specific immunity, dependent on T cell help.
Keywords: Dendritic Cells
CD4-Positive T-Lymphocytes
T-Lymphocytes, Cytotoxic
Mice, Knockout
Melanoma, Experimental
Lectins, C-Type
Receptors, Immunologic
Adjuvants, Immunologic
Antigens, Neoplasm
Description: Bijun Zeng, Anton P.J. Middelberg, Adrian Gemiarto, Kelli MacDonald, Alan G. Baxter, Meghna Talekar, Davide Moi, Kirsteen M. Tullett, Irina Caminschi, Mireille H. Lahoud, Roberta Mazzieri, Riccardo Dolcetti and Ranjeny Thomas
Rights: Copyright © 2018, American Society for Clinical Investigation
DOI: 10.1172/JCI96791
Grant ID:
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