Prothymosin α and a prothymosin α-derived peptide enhance T(H)1-type immune responses against defined HER-2/neu epitopes.
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.
Department of Animal and Human Physiology, Faculty of Biology, University of Athens, Athens 15784, Greece. rtsitsil@biol.uoa.gr.
Kyriaki
K
Ioannou
Evelyna
E
Derhovanessian
Eleni
E
Tsakiri
Pinelopi
P
Samara
Hubert
H
Kalbacher
Wolfgang
W
Voelter
Ioannis P
IP
Trougakos
Graham
G
Pawelec
Ourania E
OE
Tsitsilonis
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D016219:Immunotherapy, Adoptive / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013947:Thymosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D000939:Epitopes; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; D011498:Protein Precursors; D018719:Erb-b2 Receptor Tyrosine Kinases; D017472:Receptors, Interleukin-1; D013947:Thymosin; D051197:Toll-Like Receptor 4; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; C040782:prothymosin alpha