Abstract A26: Potent Th cell epitope modified HER2/neu dendritc cell vaccine magnify antitumor responses in HER2/neu tolerance transgenic mice.
Authors: Chen Yuxiu , Xie Yufeng , Xiang Jim 
Published: August 2014

Breast cancer is the most common cancer among women. Of all breast cancers cases, approximately 30% have amplifications of the self-antigen HER2/neu. Later studies have also found antibody response and T cell response specific for HER2/neu in cancer patients, indicating HER2/neu may be a good target for active immunotherapy. Following studies on HER2/neu targeted immunotherapeutic strategies all have been proven to be incapable of breaking tolerance towards HER2/neu, and couldn't elicit adequate antitumor immunity in curing HER2/neu positive breast cancer in spontaneously developed tumor transgenic mouse model, although both humeral and cellular immune responses could be detected. CD4+ T helper cells play an essential role in antitumor immunity. Reports have demonstrated that CD8+ T cells at resting or non-responsive state can be activated by providing cytokines and co-stimulatory signals, suggesting T cell help activation is crucial in breaking CD8+ CTL tolerance. The tetanus toxoid Th P30 has been found to be a universal and potent epitope in sensitizing and proliferating CD4+ T cells ex vivo.

In this study, to evaluate the P30 effect on vaccine efficacy, we constructed two recombinant AdVs (AdVOVA-P30 and AdVHER2/neu-P30) expressing ovalbumin (OVA)-P30 and HER2/neu-P30, and two AdV transduced DC vaccines (DCOVA-P30 and DCHER2/neu-P30), and then compared the the immunization efficacy between vaccines with and without Th epitope P30 in the same vaccine modality in wild-type C57BL6 mouse model, a mouse model for OVA/OVA-P30 system study, and FVNneuN mouse model, a in vivo murine tumor model expressing the rat neu Ag. We demonstrate that both AdVOVA and AdVOVA-P30 vaccines could stimulate super high level of OVA-specific CD8+ T lymphocytes (CTLs) in wild-type C56BL/6 mice, but with no significant defference. However, when assess the immune responses induced by DCOVA and DCOVA-P30, we found both of CD4+ T cell and OVA-sepcific CD8+ T cell responses induced by DCOVA-P30 are significantly higher than that of DCOVA. Futher study on in vivo cytotoxic assay also confirmed this finding. Althogh both of DCOVA and DCOVA-P30 vaccines could lead to preventive long-term immunity against OVA-expressing BL6-10OVA melanoma in metastasizing in wild-type C56BL/6 mice, therapeutic antitumor immunity induced by DCOVA-P30 vaccine could kill significantly higher amount of pre-existing BL6-10OVA melanoma, suggesting that with the help of the universal potent Th epitope P30, vaccine efficacy could be enhanced. When apply such vaccine modality to HER2/neu-tolerance mouse model FVNneuN so as to enhace the anti-HER2/neu immunity, we also found DCneu-P30 could stimulate stronger CD8+ T cell response that of DCHER2/neu, leading to signigicantly stronger preventive antitumor immunity against HER2/neu expressing tumor cell line from FVNneuN, prolonging the life span of FVNneuN mice.

Citation Format: Yuxiu Chen, Yufeng Xie, Jim Xiang. Potent Th cell epitope modified HER2/neu dendritc cell vaccine magnify antitumor responses in HER2/neu tolerance transgenic mice. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A26.