EBV oncogene N-LMP1 induces CD4 T cell-mediated angiogenic blockade in the murine tumor model

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (9), p.4577-4587
• Main Authors: Wu, Tzong-Shoon, Wang, Lian-Chen, Liu, Shu-Chen, Hsu, Ting-Yu, Lin, Chun-Yen, Feng, Gou-Jin, Chen, Jian-Ming, Liu, Hao-Ping, Chung, I-Che, Yen, Tzu-Chen, Chang, Yu-Sun, Liao, Shuen-Kuei, Chang, Chen, Chow, Kai-Ping N
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Line, Tumor; Dendritic Cells - immunology; Disease Models, Animal; Disease Progression; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Epstein-Barr virus; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - immunology; Lymphocyte Activation - immunology; Male; Mice; Mice, Knockout; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - virology; Neovascularization, Pathologic - immunology; Peptide Fragments - chemistry; Peptide Fragments - immunology; Viral Matrix Proteins - chemistry; Viral Matrix Proteins - genetics; Viral Matrix Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400794

Antivascular immunity may provide long-term protection by preventing neovascularization that precedes tumor progression. Although the tumorigenesis promoted by EBV-encoded oncogene latent membrane protein 1 derived from Taiwanese nasopharyngeal carcinoma (N-LMP1) has been demonstrated, the potential of N-LMP1 for inducing immune surveillance remains elusive. In this article, we describe the immunogenicity of N-LMP1 (1510) and its induction of antivascular immunity in a transplantable tumor model in immunocompetent BALB/c mice. The immunogenicity of N-LMP1 was evaluated on the basis of tumor rejection following immunization. The impact of the immunization on the dynamics of tumor angiogenesis was assessed by temporal noninvasive dynamic contrast-enhanced magnetic resonance imaging and was further confirmed by histologic study and vascular count. Through the experiments of in vivo depletion and adoptive transfer, CD4 T cells were identified as effectors that depend on IFN-γ for tumor prevention. The response was further verified by the identification of an MHC H-2 I-E(d)-restricted peptide derived from N-LMP1 and by the immunization of mice with N-LMP1 peptide-loaded dendritic cells. These studies provide insight into N-LMP1-specific immunity in vivo, which suggests that CD4 T cells may play an important role in angiogenic surveillance against LMP1-associated cancer via tumor stroma targeting.