In vivo imaging of an inducible oncogenic tumor antigen visualizes tumor progression and predicts CTL tolerance.
Visualizing oncogene/tumor Ag expression by noninvasive imaging is of great interest for understanding processes of tumor development and therapy. We established transgenic (Tg) mice conditionally expressing a fusion protein of the SV40 large T Ag and luciferase (TagLuc) that allows monitoring of oncogene/tumor Ag expression by bioluminescent imaging upon Cre recombinase-mediated activation. Independent of Cre-mediated recombination, the TagLuc gene was expressed at low levels in different tissues, probably due to the leakiness of the stop cassette. The level of spontaneous TagLuc expression, detected by bioluminescent imaging, varied between the different Tg lines, depended on the nature of the Tg expression cassette, and correlated with Tag-specific CTL tolerance. Following liver-specific Cre-loxP site-mediated excision of the stop cassette that separated the promoter from the TagLuc fusion gene, hepatocellular carcinoma development was visualized. The ubiquitous low level TagLuc expression caused the failure of transferred effector T cells to reject Tag-expressing tumors rather than causing graft-versus-host disease. This model may be useful to study different levels of tolerance, monitor tumor development at an early stage, and rapidly visualize the efficacy of therapeutic intervention versus potential side effects of low-level Ag expression in normal tissues.
Institute of Immunology, Charité Campus Benjamin Franklin, Berlin, Germany.
Christian
C
Buschow
Jehad
J
Charo
Kathleen
K
Anders
Christoph
C
Loddenkemper
Ana
A
Jukica
Wisam
W
Alsamah
Cynthia
C
Perez
Gerald
G
Willimsky
Thomas
T
Blankenstein
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D019426:Integrases / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011237:Predictive Value of Tests; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D015514:Oncogene Proteins, Fusion; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases