Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine

Matthew Timothy Hueman, Alexander Stojadinovic, Catherine E. Storrer, Rebecca J. Foley, Jennifer M. Gurney, Craig D. Shriver, Sathibalan Ponniah, George E. Peoples

Research output: Contribution to journalArticle

Abstract

Purpose. We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses. Experimental design. Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu + tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-β levels. Results. BrCa patients have a greater percentage of circulating Treg (CD4+CD25 +, 4.45% versus 2.96%; p = 0.007) than normal subjects. HLA-A2 + BrCa patients had more Treg compared to the HLA-A2 - BrCa patients (CD4+CD25+, 5.63% versus 3.28%; p = 0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81%; p = 0.03). However, Treg were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81%; p <0.0001). Furthermore, activated Treg also decreased (CD4+CD25 +CD69+, 0.23% versus 0.08%; p = 0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu + tumor cytotoxicity. Serum TGF-β levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p = 0.007). Four of seven vaccinated patients showed decreased serum TGF-β levels post-vaccination. Conclusions. Treg, are increased in BrCa patients along with serum levels of TGF-β. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-β levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.

Original languageEnglish (US)
Pages (from-to)17-29
Number of pages13
JournalBreast Cancer Research and Treatment
Volume98
Issue number1
DOIs
StatePublished - Jul 2006
Externally publishedYes

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Granulocyte-Macrophage Colony-Stimulating Factor
Vaccination
Vaccines
Breast Neoplasms
T-Lymphocytes
Peptides
HLA-A2 Antigen
Serum
Neoplasms
Subunit Vaccines
Regulatory T-Lymphocytes
Antigen-Antibody Complex
Flow Cytometry
Research Design
Clinical Trials

Keywords

  • CD4CD25 T cells
  • E75
  • HER2/neu
  • Peptide vaccine
  • Regulatory T cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. / Hueman, Matthew Timothy; Stojadinovic, Alexander; Storrer, Catherine E.; Foley, Rebecca J.; Gurney, Jennifer M.; Shriver, Craig D.; Ponniah, Sathibalan; Peoples, George E.

In: Breast Cancer Research and Treatment, Vol. 98, No. 1, 07.2006, p. 17-29.

Research output: Contribution to journalArticle

Hueman, Matthew Timothy ; Stojadinovic, Alexander ; Storrer, Catherine E. ; Foley, Rebecca J. ; Gurney, Jennifer M. ; Shriver, Craig D. ; Ponniah, Sathibalan ; Peoples, George E. / Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. In: Breast Cancer Research and Treatment. 2006 ; Vol. 98, No. 1. pp. 17-29.
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abstract = "Purpose. We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses. Experimental design. Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu + tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-β levels. Results. BrCa patients have a greater percentage of circulating Treg (CD4+CD25 +, 4.45{\%} versus 2.96{\%}; p = 0.007) than normal subjects. HLA-A2 + BrCa patients had more Treg compared to the HLA-A2 - BrCa patients (CD4+CD25+, 5.63{\%} versus 3.28{\%}; p = 0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81{\%}; p = 0.03). However, Treg were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81{\%}; p <0.0001). Furthermore, activated Treg also decreased (CD4+CD25 +CD69+, 0.23{\%} versus 0.08{\%}; p = 0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu + tumor cytotoxicity. Serum TGF-β levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p = 0.007). Four of seven vaccinated patients showed decreased serum TGF-β levels post-vaccination. Conclusions. Treg, are increased in BrCa patients along with serum levels of TGF-β. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-β levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.",
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author = "Hueman, {Matthew Timothy} and Alexander Stojadinovic and Storrer, {Catherine E.} and Foley, {Rebecca J.} and Gurney, {Jennifer M.} and Shriver, {Craig D.} and Sathibalan Ponniah and Peoples, {George E.}",
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T1 - Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine

AU - Hueman, Matthew Timothy

AU - Stojadinovic, Alexander

AU - Storrer, Catherine E.

AU - Foley, Rebecca J.

AU - Gurney, Jennifer M.

AU - Shriver, Craig D.

AU - Ponniah, Sathibalan

AU - Peoples, George E.

PY - 2006/7

Y1 - 2006/7

N2 - Purpose. We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses. Experimental design. Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu + tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-β levels. Results. BrCa patients have a greater percentage of circulating Treg (CD4+CD25 +, 4.45% versus 2.96%; p = 0.007) than normal subjects. HLA-A2 + BrCa patients had more Treg compared to the HLA-A2 - BrCa patients (CD4+CD25+, 5.63% versus 3.28%; p = 0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81%; p = 0.03). However, Treg were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81%; p <0.0001). Furthermore, activated Treg also decreased (CD4+CD25 +CD69+, 0.23% versus 0.08%; p = 0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu + tumor cytotoxicity. Serum TGF-β levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p = 0.007). Four of seven vaccinated patients showed decreased serum TGF-β levels post-vaccination. Conclusions. Treg, are increased in BrCa patients along with serum levels of TGF-β. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-β levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.

AB - Purpose. We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses. Experimental design. Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu + tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-β levels. Results. BrCa patients have a greater percentage of circulating Treg (CD4+CD25 +, 4.45% versus 2.96%; p = 0.007) than normal subjects. HLA-A2 + BrCa patients had more Treg compared to the HLA-A2 - BrCa patients (CD4+CD25+, 5.63% versus 3.28%; p = 0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81%; p = 0.03). However, Treg were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81%; p <0.0001). Furthermore, activated Treg also decreased (CD4+CD25 +CD69+, 0.23% versus 0.08%; p = 0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu + tumor cytotoxicity. Serum TGF-β levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p = 0.007). Four of seven vaccinated patients showed decreased serum TGF-β levels post-vaccination. Conclusions. Treg, are increased in BrCa patients along with serum levels of TGF-β. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-β levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.

KW - CD4CD25 T cells

KW - E75

KW - HER2/neu

KW - Peptide vaccine

KW - Regulatory T cells

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