Prevention of Spontaneous Tumor Development in a ret Transgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan

¹Center of Microbiology, Biochemistry, and Pharmacology, School of Pharmaceutical Science, Sun Yat-sen University; ²Department of Medical Genetics and Cell Biology, Guangzhou Medical College; ³College of Pharmacy, Jinan University, Guangzhou, People's Republic of China and ⁴School of Pharmacy, Wenzhou Medical College, Wenzhou, People's Republic of China

^* To whom correspondence should be addressed. E-mail: dujun{at}mail.sysu.edu.cn.

	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. [Cancer Res 2009;69(9):3963–70]

Key Words: Rearranged during transfection, Indoleamine 2,3-Dioxygenase, Tumor Immune Tolerance, 1-Methyl Tryptophan, Spontaneous Tumor