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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-05, Vol.69 (9), p.3963-3970
• Main Authors: Zeng, Jun, Cai, Shaohui, Yi, Yanmei, He, Yuwen, Wang, Zhen, Jiang, Guangmin, Li, Xiaokun, Du, Jun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CpG Islands - genetics; CpG Islands - immunology; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis; Lymph Nodes - enzymology; Lymphocyte Activation; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental - immunology; Neoplasms, Experimental - prevention & control; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-ret - biosynthesis; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - immunology; Spleen - enzymology; T-Lymphocytes - immunology; Tryptophan - analogs & derivatives; Tryptophan - pharmacology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2476

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.