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

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy.
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Zeng B, Middelberg AP, Gemiarto A, MacDonald K, Baxter AG, Talekar M, Moi D, Tullett KM, Caminschi I, Lahoud MH, Mazzieri R, Dolcetti R, Thomas R,


Zeng B, Middelberg AP, Gemiarto A, MacDonald K, Baxter AG, Talekar M, Moi D, Tullett KM, Caminschi I, Lahoud MH, Mazzieri R, Dolcetti R, Thomas R, (click to view)

Zeng B, Middelberg AP, Gemiarto A, MacDonald K, Baxter AG, Talekar M, Moi D, Tullett KM, Caminschi I, Lahoud MH, Mazzieri R, Dolcetti R, Thomas R,

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The Journal of clinical investigation 2018 04 09() doi 10.1172/JCI96791

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.

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