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

Bijun Zeng, Anton P J Middelberg, Adrian Gemiarto, Kelli P A MacDonald, Alan G Baxter, Meghna Talekar, Davide Moi, Kirsteen M. Tullett, Irene Caminschi, Mireille H. Lahoud, Roberta Mazzieri, Riccardo Dolcetti, Ranjeny Thomas

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1971-1984
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Zeng, B., Middelberg, A. P. J., Gemiarto, A., MacDonald, K. P. A., Baxter, A. G., Talekar, M., ... Thomas, R. (2018). Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. Journal of Clinical Investigation, 128(5), 1971-1984. https://doi.org/10.1172/JCI96791
Zeng, Bijun ; Middelberg, Anton P J ; Gemiarto, Adrian ; MacDonald, Kelli P A ; Baxter, Alan G ; Talekar, Meghna ; Moi, Davide ; Tullett, Kirsteen M. ; Caminschi, Irene ; Lahoud, Mireille H. ; Mazzieri, Roberta ; Dolcetti, Riccardo ; Thomas, Ranjeny. / Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1971-1984.
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title = "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.",
author = "Bijun Zeng and Middelberg, {Anton P J} and Adrian Gemiarto and MacDonald, {Kelli P A} and Baxter, {Alan G} and Meghna Talekar and Davide Moi and Tullett, {Kirsteen M.} and Irene Caminschi and Lahoud, {Mireille H.} and Roberta Mazzieri and Riccardo Dolcetti and Ranjeny Thomas",
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Zeng, B, Middelberg, APJ, Gemiarto, A, MacDonald, KPA, Baxter, AG, Talekar, M, Moi, D, Tullett, KM, Caminschi, I, Lahoud, MH, Mazzieri, R, Dolcetti, R & Thomas, R 2018, 'Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy' Journal of Clinical Investigation, vol. 128, no. 5, pp. 1971-1984. https://doi.org/10.1172/JCI96791

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy. / Zeng, Bijun; Middelberg, Anton P J; Gemiarto, Adrian; MacDonald, Kelli P A; Baxter, Alan G; Talekar, Meghna; Moi, Davide; Tullett, Kirsteen M.; Caminschi, Irene; Lahoud, Mireille H.; Mazzieri, Roberta; Dolcetti, Riccardo; Thomas, Ranjeny.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1971-1984.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zeng, Bijun

AU - Middelberg, Anton P J

AU - Gemiarto, Adrian

AU - MacDonald, Kelli P A

AU - Baxter, Alan G

AU - Talekar, Meghna

AU - Moi, Davide

AU - Tullett, Kirsteen M.

AU - Caminschi, Irene

AU - Lahoud, Mireille H.

AU - Mazzieri, Roberta

AU - Dolcetti, Riccardo

AU - Thomas, Ranjeny

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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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