Steroidogenic acute regulatory (StAR)-directed immunotherapy protects against tumor growth of StAR-expressing Sp2-0 cells in a rodent adrenocortical carcinoma model.
Adrenocortical carcinoma (ACC) is a highly malignant tumor with poor response to classical antitumor therapy. Steroidogenic acute regulatory (StAR) protein is expressed in most human ACCs. The aim of this study was to induce antitumoral T cells directed against StAR in a murine tumor model. Because a suitable syngenic adrenocortical mouse tumor model is lacking, we established a clone of the mouse myeloma Sp2-0 tumor cell line stably expressing murine StAR (Sp2-mStAR). Using repeated im injections of plasmid DNA encoding mStAR followed by infection with a recombinant vaccinia virus (rVV) expressing mStAR, we induced a cytotoxic T-cell response as measured by enzyme-linked immunospot assay. To demonstrate antitumor activity of the vaccination procedure, mice were treated as follows: group A, mice immunized with plasmids and rVV encoding mStAR receiving Sp2-mStAR cells; control group B, mice immunized with the empty plasmid and the empty rVV receiving Sp2-mStAR cells; control group C, mice immunized with the empty plasmid and rVV encoding P450 side-chain cleavage enzyme receiving Sp2-mStAR cells; and control group D, mice immunized with plasmid and rVV encoding mStAR receiving parental Sp2-0 cells. A high proportion (89-100%) of the control groups B, C, and D developed subcutaneous tumors. In contrast, immunization specific for mStAR (group A) was highly protective against tumor growth (percentage of tumor-free animals, 67%; P < 0.001 vs. controls). In summary, these results show that T-cell tolerance toward mStAR can be broken, resulting in antitumoral immunity. Thus, StAR represents a candidate target antigen for immunotherapeutic strategies against ACC.
Ortmann
Dörte
D
Department of Internal Medicine 2, University Hospital of Freiburg, Germany.
Hausmann
Jürgen
J
Beuschlein
Felix
F
Schmenger
Kai
K
Stahl
Maik
M
Geissler
Michael
M
Reincke
Martin
M
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007109:Immunity; D007114:Immunization; D007117:Immunization, Secondary; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003345:Corticosterone