Background: The mechanism of spontaneous regression of neuroblastoma has been unclear. There are four major pathways that are reported to explain the spontaneous regression. That is: immune mediated cell killing (1), neurotrophin deprivation(2), loss of telomerase activity(3) and alterations in epigenetic regulation(4). However, there is no clinical evidence, and no animal models have been developed to investigate the involvement of immune systems, especially natural antibodies, against neuroblastoma.
Methods: We performed an immunological analysis of homo- and heterozygous TH-MYCN transgenic mice as a model of aggressive neuroblastoma. The tumor cells obtained from TH-MYCN mice were incubated with mouse plasma obtained from TH-MYCN mice and stained by anti-mouse IgG/ IgM, and the fluorescene was measured by flow cytometry. The tumors were detected by ultrasound.
Results: Approximately half of the heterozygous mice developed intraabdominal neuroblastoma and died within 20-week-age. On the other hand, microscopic findings of the superior mesenteric ganglion in 2 to 3-week-age mice revealed that the ganglion of all individuals contains solitary or multiple tumor foci, and then the frequency of tumorigenesis decreases, indicating the spontaneous regression might be occurred in half of this model. Mice with no or small (<5mm) tumors showed higher antibody titers in plasma than mice with large (>5mm) tumors. A significant negative correlation was observed between the tumor diameter and the titer of anti-tumor antibody. Surprisingly, wild type mice had similar amount of anti-tumor IgG/IgM. And, the plasma obtained from wild type mice has higher complement dependent cytotoxicity against neuroblastoma cells comparing to the plasma obtained from tumor developing mice.
Conclusion: We revealed that TH-MYCN transgenic mice have a functional antibody against neuroblastoma that influences the disease prognosis. The antibody strongly correlates to the spontaneous regression of neuroblastoma. TH-MYCN transgenic mice will be an important tool for elucidating the mechanism of spontaneous regression of neuroblastoma.