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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 - May 1 2018

Fingerprint

Immunotherapy
Dendritic Cells
Antigens
T-Lymphocytes
Experimental Melanomas
Cytotoxic T-Lymphocytes
Neoplasm Antigens
Epitopes
CD8 Antigens
Neoplasms
CD4 Antigens
Viral Tumor Antigens
Growth
Antibody Formation
Immunity
Cell Proliferation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zeng, B., Middelberg, A. P. J., Gemiarto, A., MacDonald, K., 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

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; Thomas, Ranjeny.

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

Research output: Contribution to journalArticle

Zeng, B, Middelberg, APJ, Gemiarto, A, MacDonald, K, 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
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 ; 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.
@article{405f57f60ab64588afdd89428b5efe97,
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 Kelli MacDonald and Baxter, {Alan G.} and Meghna Talekar and Davide Moi and Tullett, {Kirsteen M.} and Irina Caminschi and Lahoud, {Mireille H.} and Roberta Mazzieri and Riccardo Dolcetti and Ranjeny Thomas",
year = "2018",
month = "5",
day = "1",
doi = "10.1172/JCI96791",
language = "English",
volume = "128",
pages = "1971--1984",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy

AU - Zeng, Bijun

AU - Middelberg, Anton P.J.

AU - Gemiarto, Adrian

AU - MacDonald, Kelli

AU - Baxter, Alan G.

AU - Talekar, Meghna

AU - Moi, Davide

AU - Tullett, Kirsteen M.

AU - Caminschi, Irina

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85046458777&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046458777&partnerID=8YFLogxK

U2 - 10.1172/JCI96791

DO - 10.1172/JCI96791

M3 - Article

AN - SCOPUS:85046458777

VL - 128

SP - 1971

EP - 1984

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -