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

Kyriaki Ioannou,Wolfgang Voelter,Pinelopi Samara,Ioannis P Trougakos,Hubert Kalbacher,Eleni Tsakiri,Ourania E Tsitsilonis,Graham Pawelec,Evelyna Derhovanessian

doi:10.1186/1471-2172-14-43

Kyriaki Ioannou, Wolfgang Voelter + Show 7 more

Open Access

https://doi.org/10.1186/1471-2172-14-43

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Abstract

BackgroundActive 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.ResultsMonocyte-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.ConclusionsOur 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.

Highlights

Active cancer immunotherapies are beginning to yield clinical benefit, especially those using peptidepulsed dendritic cells (DCs)
Phenotype of and cytokine production by Prothymosin alpha (proTα)- or proTα(100–109)-matured DCs We have previously shown that proTα and proTα(100–109) efficiently mature human DCs in vitro, as indicated by the induction of surface expression of established DC
In agreement with our previous study [23], Immature DCs (iDCs) matured with either proTα or its decapeptide presented a similar phenotype to LPS- or tumor necrosis factor (TNF)-α-matured DCs, upregulating the expression of all co-stimulatory molecules (p < 0.05-0.001, compared to iDCs; Figure 1) and downregulating CD14 (p < 0.01, compared to iDCs)

Summary

Introduction

Active cancer immunotherapies are beginning to yield clinical benefit, especially those using peptidepulsed dendritic cells (DCs). Administering defined tumor-derived epitopes to cancer patients for the activation of helper and cytotoxic T cells has been shown to enhance anti-cancer immune responses in vivo and in some cases to lead to has been proven successful only when vaccinating against common pathogens [8]. The presence of tumor-associated suppressive factors impairs endogenous DC functions [9], a condition that can be bypassed only by the adoptive transfer of ex vivo matured immunocompetent DCs [10,11]. From damaged cells, signal through TLR-4, sensitize DCs and promote adaptive immune responses [17]. This functional dualism, in and out of the cell, characterizes prothymosin alpha (proTα)

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