Prevention of spontaneous tumor development in a ret transgenic mouse model by ret peptide vaccination with indoleamine 2,3-dioxygenase inhibitor 1-methyl tryptophan.
The present study investigated an immunotherapeutic strategy for rearranged during transfection proto-oncogene (ret)-associated carcinomas in a transgenic MT/ret 304/B6 mouse model in which spontaneous tumors develop due to overexpression of the ret gene. A Ret peptide vaccine comprising an extracellular fragment of Ret protein and Th1-polarized immunoregulator CpG oligonucleotide (1826) induced strong and specific cellular and humoral immune responses in wild-type C57BL/6 mice, showing that the Ret peptide has a strong immunogenic potential as part of an antitumor vaccine. In MT/ret 304/B6 mice, however, the vaccine was only modestly effective as an inducer of the humoral immune response, and it failed to elicit a T-cell response. An immunohistochemical analysis revealed marked indoleamine 2,3-dioxygenase expression after immunization with Ret peptide vaccine in the lymph nodes and spleens of MT/ret 304/B6 mice. The systemic administration of the potent inhibitor of indoleamine 2,3-dioxygenase 1-methyl tryptophan (1MT) along with Ret vaccine produced a significant increase in tumor-specific cytotoxic activity. A delay in spontaneous tumor development was also observed in the MT/ret 304/B6 mice to which the Ret vaccine and 1MT were administered. These results indicate that an improved Ret vaccine composed of Ret peptide plus CpG oligonucleotide plus 1MT is a potential therapeutic strategy for treatment of ret-associated carcinomas.
Zeng
Jun
J
Center of Microbiology, Biochemistry, and Pharmacology, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, People's Republic of China..
Cai
Shaohui
S
Yi
Yanmei
Y
He
Yuwen
Y
Wang
Zhen
Z
Jiang
Guangmin
G
Li
Xiaokun
X
Du
Jun
J
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008198:Lymph Nodes / Q000201:enzymology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000201:enzymology; D013601:T-Lymphocytes / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D019496:Cancer Vaccines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014364:Tryptophan; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human