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

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

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 7

Clec9A-TNE encapsulating immunogenic neoepitopes generate antigen-specific T cell responses and suppress the growth of B16-F10 tumors.

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Clec9A-TNE encapsulating immunogenic neoepitopes generate antigen-specif...
(A) C57BL/6 mice (n = 7) were inoculated s.c. with B16-F10, then treated with WH-TNE or G-actin–TNE loaded with a pool of B16-F10 mutated epitopes, as described in Methods, or left untreated. Mean tumor size is plotted over time for each group. (B) C57BL/6 mice (n = 10) were inoculated s.c. with B16-F10, then treated with WH-TNE or G-actin–TNE loaded with a pool of B16-F10 mutated epitopes or left untreated 8 days after tumor inoculation. Survival curves of tumor-bearing mice are shown. (C) Peripheral blood mononuclear cells were stimulated with B16 epitopes or endogenous survivin peptide, and IFN-γ production was measured by ELISPOT. (D) Tumor growth (± CD4-depleting antibody) in mice inoculated s.c. with B16-F10 and treated with WH-TNE loaded with the pool of B16-F10 mutated epitopes or left untreated (n = 7). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA test. Survival analyses used the Mantel-Cox log-rank test.