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Open Access Research article

Prothymosin α and a prothymosin α-derived peptide enhance TH1-type immune responses against defined HER-2/neu epitopes

Kyriaki Ioannou1, Evelyna Derhovanessian2, Eleni Tsakiri3, Pinelopi Samara1, Hubert Kalbacher4, Wolfgang Voelter4, Ioannis P Trougakos3, Graham Pawelec2 and Ourania E Tsitsilonis1*

Author Affiliations

1 Department of Animal and Human Physiology, Faculty of Biology, University of Athens, Athens 15784, Greece

2 Department of Internal Medicine II, Centre for Medical Research, University of Tübingen, Tübingen 72072, Germany

3 Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens 15784, Greece

4 Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen 72072, Germany

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BMC Immunology 2013, 14:43  doi:10.1186/1471-2172-14-43

Published: 22 September 2013

Abstract

Background

Active cancer immunotherapies are beginning to yield clinical benefit, especially those using peptide-pulsed dendritic cells (DCs). Different adjuvants, including Toll-like receptor (TLR) agonists, commonly co-administered to cancer patients as part of a DC-based vaccine, are being widely tested in the clinical setting. However, endogenous DCs in tumor-bearing individuals are often dysfunctional, suggesting that ex vivo educated DCs might be superior inducers of anti-tumor immune responses. We have previously shown that prothymosin alpha (proTα) and its immunoreactive decapeptide proTα(100–109) induce the maturation of human DCs in vitro. The aim of this study was to investigate whether proTα- or proTα(100–109)-matured DCs are functionally competent and to provide preliminary evidence for the mode of action of these agents.

Results

Monocyte-derived DCs matured in vitro with proTα or proTα(100–109) express co-stimulatory molecules and secrete pro-inflammatory cytokines. ProTα- and proTα(100–109)-matured DCs pulsed with HER-2/neu peptides induce TH1-type immune responses, prime autologous naïve CD8-positive (+) T cells to lyse targets expressing the HER-2/neu epitopes and to express a polyfunctional profile, and stimulate CD4+ T cell proliferation in an HER-2/neu peptide-dependent manner. DC maturation induced by proTα and proTα(100–109) is likely mediated via TLR-4, as shown by assessing TLR-4 surface expression and the levels of the intracellular adaptor molecules TIRAP, MyD88 and TRIF.

Conclusions

Our results suggest that proTα and proTα(100–109) induce both the maturation and the T cell stimulatory capacity of DCs. Although further studies are needed, evidence for a possible proTα and proTα(100–109) interaction with TLR-4 is provided. The initial hypothesis that proTα and the proTα-derived immunoactive decapeptide act as “alarmins”, provides a rationale for their eventual use as adjuvants in DC-based anti-cancer immunotherapy.

Keywords:
Prothymosin alpha; Immunoreactive peptide; Dendritic cells; TH1 immune responses; TLR-4; Adjuvant; HER-2/neu peptides