Antibody association with HER-2/neu-targeted vaccine enhances CD8 + T cell responses in mice through Fc-mediated activation of DCs

Peter S. Kim, Todd D Armstrong, Hong Song, Matthew E. Wolpoe, Vivian Weiss, Elizabeth A. Manning, Lan Qing Huang, Satoshi Murata, George Sgouros, Leisha A. Emens, R. Todd Reilly, Elizabeth Jaffee

Research output: Contribution to journalArticle

Abstract

The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8+ neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8 + T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)1700-1711
Number of pages12
JournalJournal of Clinical Investigation
Volume118
Issue number5
DOIs
StatePublished - May 1 2008

Fingerprint

Vaccines
T-Lymphocytes
Antibodies
Granulocyte-Macrophage Colony-Stimulating Factor
Neoplasms
Immune Tolerance
Cancer Vaccines
Tumor Microenvironment
Autoantigens
Neoplasm Antigens
Immunosuppressive Agents
Transgenic Mice
Lymph Nodes
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Antibody association with HER-2/neu-targeted vaccine enhances CD8 + T cell responses in mice through Fc-mediated activation of DCs. / Kim, Peter S.; Armstrong, Todd D; Song, Hong; Wolpoe, Matthew E.; Weiss, Vivian; Manning, Elizabeth A.; Huang, Lan Qing; Murata, Satoshi; Sgouros, George; Emens, Leisha A.; Reilly, R. Todd; Jaffee, Elizabeth.

In: Journal of Clinical Investigation, Vol. 118, No. 5, 01.05.2008, p. 1700-1711.

Research output: Contribution to journalArticle

Kim, Peter S. ; Armstrong, Todd D ; Song, Hong ; Wolpoe, Matthew E. ; Weiss, Vivian ; Manning, Elizabeth A. ; Huang, Lan Qing ; Murata, Satoshi ; Sgouros, George ; Emens, Leisha A. ; Reilly, R. Todd ; Jaffee, Elizabeth. / Antibody association with HER-2/neu-targeted vaccine enhances CD8 + T cell responses in mice through Fc-mediated activation of DCs. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 5. pp. 1700-1711.
@article{c5275b6b142844beb8b3352bdaf5c3f5,
title = "Antibody association with HER-2/neu-targeted vaccine enhances CD8 + T cell responses in mice through Fc-mediated activation of DCs",
abstract = "The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100{\%} of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8+ neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8 + T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.",
author = "Kim, {Peter S.} and Armstrong, {Todd D} and Hong Song and Wolpoe, {Matthew E.} and Vivian Weiss and Manning, {Elizabeth A.} and Huang, {Lan Qing} and Satoshi Murata and George Sgouros and Emens, {Leisha A.} and Reilly, {R. Todd} and Elizabeth Jaffee",
year = "2008",
month = "5",
day = "1",
doi = "10.1172/JCI34333",
language = "English (US)",
volume = "118",
pages = "1700--1711",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Antibody association with HER-2/neu-targeted vaccine enhances CD8 + T cell responses in mice through Fc-mediated activation of DCs

AU - Kim, Peter S.

AU - Armstrong, Todd D

AU - Song, Hong

AU - Wolpoe, Matthew E.

AU - Weiss, Vivian

AU - Manning, Elizabeth A.

AU - Huang, Lan Qing

AU - Murata, Satoshi

AU - Sgouros, George

AU - Emens, Leisha A.

AU - Reilly, R. Todd

AU - Jaffee, Elizabeth

PY - 2008/5/1

Y1 - 2008/5/1

N2 - The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8+ neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8 + T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.

AB - The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8+ neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8 + T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.

UR - http://www.scopus.com/inward/record.url?scp=43049144967&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43049144967&partnerID=8YFLogxK

U2 - 10.1172/JCI34333

DO - 10.1172/JCI34333

M3 - Article

C2 - 18398507

AN - SCOPUS:43049144967

VL - 118

SP - 1700

EP - 1711

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -