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Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy
Bijun Zeng, … , Riccardo Dolcetti, Ranjeny Thomas
Bijun Zeng, … , Riccardo Dolcetti, Ranjeny Thomas
Published February 27, 2018
Citation Information: J Clin Invest. 2018;128(5):1971-1984. https://doi.org/10.1172/JCI96791.
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Research Article Immunology Oncology Article has an altmetric score of 56

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy

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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.

Authors

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, Ranjeny Thomas

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Figure 5

E6/E7–Clec9A-TNE but not E6/E7–CpG vaccination is immunogenic and controls TC1 tumor growth.

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E6/E7–Clec9A-TNE but not E6/E7–CpG vaccination is immunogenic and contro...
(A) C57BL/6 mice (n = 10) developing tumor after s.c. injection of TC1 were treated with E6/E7–WH-TNE or E6/E7 with 10 μg CpG or left untreated. Mean tumor size is plotted over time for each group, and individual mice are shown. (B) Peripheral blood mononuclear cells were stimulated with HPV16 E7 aa49–57 (RAHYNIVTF) peptide, and IFN-γ production was quantified by ELISPOT. (C) Experimental design as in A; survival curves of tumor-bearing mice are shown. (D) Organs were harvested from untreated, DiR-labeled E6/E7–WH-TNE–treated, or DiR-labeled E6/E7–isotype-TNE–treated TC1 tumor–bearing mice. Images show distribution of DiR-labeled TNE in lung, liver, spleen, inguinal lymph node (ILN), and tumor. *P < 0.05; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA test. Survival analyses used the Mantel-Cox log-rank test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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