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

Zeng, Bijun, Middelberg, Anton P.J., Gemiarto, Adrian, Macdonald, Kelli, Baxter, Alan G., Talekar, Meghna, Moi, Davide, Tullett, Kirsteen M., Caminschi, Irina, Lahoud, Mireille H., Mazzieri, Roberta, Dolcetti, Riccardo, and Thomas, Ranjeny (2018) Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. Journal of Clinical Investigation, 128 (5). pp. 1971-1984.

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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-alpha. 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.

Item ID: 53784
Item Type: Article (Research - C1)
ISSN: 1558-8238
Copyright Information: Copyright © 2019 American Society for Clinical Investigation.
Funders: National Health and Medical Research Council (NHMRC), Australian Skin and Skin Cancer Centre (ASSCC), Arthritis Queensland (AQ), Bill and Janini Amiet Fellowship
Projects and Grants: NHMRC 1083192, NHMRC 1082665, NHMRC 1083747, NHMRC Research Fellowship
Date Deposited: 30 May 2018 07:30
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110706 Immunogenetics (incl Genetic Immunology) @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111203 Cancer Genetics @ 50%
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