Prevention of spontaneous tumor development in a ret transgenic mouse model by ret peptide vaccination with indoleamine 2,3-dioxygenase inhibitor 1-methyl tryptophan.

Abstract

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.

• Authors: Jun Zeng, Shaohui Cai, Yanmei Yi, Yuwen He, Zhen Wang, Guangmin Jiang, Xiaokun Li, Jun Du
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 9 Pg. 3963-70 (May 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19383920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• MAS1 protein, human
• Proto-Oncogene Mas
• Tryptophan
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Animals
• Cancer Vaccines (immunology, pharmacology)
• CpG Islands (genetics, immunology)
• Female
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, biosynthesis)
• Lymph Nodes (enzymology)
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasms, Experimental (immunology, prevention & control)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-ret (biosynthesis, genetics, immunology)
• Spleen (enzymology)
• T-Lymphocytes (immunology)
• Tryptophan (analogs & derivatives, pharmacology)