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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★

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Summary

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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Acknowledgements

This work was supported by funds from the Department of Defense to the Henry M. Jackson Foundation for the Advancement of Military Medicine (Rockville, MD) for the Clinical Breast Care Project. We thank Ms. Diane Papay and Ms. Stacy O’Neill of the Clinical Breast Care Project who provided excellent patient care and administration of the clinical trial. We also thank the staff of the Clinical Breast Care Project Immunology and Research Center for their clinical and administrative assistance.

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Authors and Affiliations

  1. Clinical Breast Care Project, Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA

    Matthew T. Hueman, Alexander Stojadinovic, Jennifer M. Gurney, Craig D. Shriver & George E. Peoples

  2. Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Alexander Stojadinovic, Catherine E. Storrer, Rebecca J. Foley, Craig D. Shriver, Sathibalan Ponniah & George E. Peoples

  3. Clinical Breast Care Project, Immunology and Research Center, Uniformed Services University of the Health Sciences, 4301 Jones Bridge, Building 139, Bethesda, MD, 20814, USA

    George E. Peoples

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  1. Matthew T. Hueman
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  2. Alexander Stojadinovic
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  3. Catherine E. Storrer
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Correspondence to George E. Peoples.

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The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense

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Hueman, M.T., Stojadinovic, A., Storrer, C.E. et al. 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★ . Breast Cancer Res Treat 98, 17–29 (2006). https://doi.org/10.1007/s10549-005-9108-5

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