Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma.
BACKGROUND
In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells.


METHODS
DCs from six patients with metastatic MTC were pulsed with tumor lysate derived from allogeneic MTC tumor cells and were heat shocked for 12 h at 40 C or kept at 37 C. Thereafter, the DCs were matured and cocultured with T cells. Finally, the cytotoxic activity of T cells against MTC tumor cells was measured in vitro.


RESULTS
In all patient samples, cytotoxic T cell responses against MTC tumor cells could be induced. Notably, heat-shocked DCs were more potent stimulators of cytotoxic T cell responses than control DCs, with T cells stimulated with heat-shocked DCs displaying a significantly increased cytotoxic activity against MTC tumor cells as compared with T cells stimulated with control DCs. In none of the experiments was a cytotoxic T cell response against unrelated pancreatic tumor cells (PANC-1) observed, using both control and heat-shocked DCs.


CONCLUSIONS
Our study shows that heat-shocking DCs may be a valuable strategy to increase the immunostimulatory capacity of DCs used for immunotherapy of MTC.
Bachleitner-Hofmann
Thomas
T
Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. thomas.bachleitner-hofmann@meduniwien.ac.at
Strohschneider
Michaela
M
Krieger
Peter
P
Sachet
Monika
M
Dubsky
Peter
P
Hayden
Hubert
H
Schoppmann
Sebastian F
SF
Pfragner
Roswitha
R
Gnant
Michael
M
Friedl
Josef
J
Stift
Anton
A
D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D002457:Cell Extracts / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007167:Immunotherapy / Q000379:methods; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D002457:Cell Extracts; D006680:HLA Antigens; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4