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EB病毒在相關癌症的腫瘤微環境中對免疫反應的調控

Immunoregulatory Roles of Epstein-Barr Virus (EBV) in the Tumor Microenvironment of Its Associated Cancers

EB病毒在相關癌症的腫瘤微環境中對免疫反應的調控

 
 

 

 

張堯 Yao Chang

助研究員 Assistant Investigator
Phone: (06) 208-3422 ext. 65261
Fax: (06) 208-3466
E-mail: yaochang@nhri.org.tw

 

 

After graduating from Department of Zoology, National Taiwan University (Taipei, Taiwan) in 1994, Yao Chang pursued his graduate training in Graduate Institute of Microbiology, National Taiwan University. Receiving the Ph.D. degree in 2000, he continued and focused his study on EBV as a Postdoctoral Fellow at the same institute. In 2005, he joined the Division of Clinical Research at NHRI.

 

Research Interests

Infection and reactivation of Epstein-Barr virus
Pathogenic mechanisms of Epstein-Barr virus-associated cancers

 

 

EBV-associated malignancies, such as nasopharyngeal carcinoma (NPC) and Hodgkin’s lymphoma, are unique for their inflammation-like microenvironment where EBV-infected tumor cells flourish in the significant presence of infiltrating leukocytes and inflammatory cytokines. Interaction between tumor cells and infiltrating immune cells is complicated and crucial for development of the cancers, and local immunosuppression has hindered the efficacy of EBV-targeted cancer immunotherapy for a long time. Our interest is to identify critical immunoregulatory roles of EBV in the tumor-infiltrate interaction.

 

EBV-infected cancer cells interact with infiltrating immune cells in unique and complicated ways. First, the tumor cells may actively attract immune cells to establish the inflammation-like microenvironment, and the invoked infiltrating cells seem to provide growth or survival advantage for tumor cells, forwarding cancer development. In addition, EBV-infected cancer cells must have adopted immunosuppressive strategies to reduce the risk of being attacked by the infiltrating leukocytes potentially targeted against EBV or tumor cells. To understand mechanisms of the local immunologic interaction is an important issue for clinical treatment of the EBV-associated malignancies.

During the past years in NHRI, I focused my study interest on whether and how EBV directs the interaction between tumor cells and infiltrating immune cells in EBV-associated cancers, especially in NPC. My laboratory has found several prominent clues indicating that EBV may initiate or promote the inflammation-like microenvironment of NPC by upregulating many chemokines and cytokines. First, we revealed that an EBV lytic transactivator Zta induces a cellular transcription factor Egr-1, which is linked to regulation of inflammation (J. Virol. 2006, 80:7748-7755). Next, we have identified that Zta upregulates a chemokine IL-8, which is involved in leukocyte infiltration, tumor growth and angiogenesis of NPC (J. Virol. 2008, 82:3679-3688). Another target of my study is LMP1, a potent EBV oncoprotein for cancer development. We have uncovered that ER stress-induced XBP-1 is an important driver for LMP1 expression in NPC, and that LMP1 is also a potent stimulator of many inflammatory cytokines in NPC cells. Besides, our preliminary data have shown that certain EBV-induced soluble factors secreted from NPC cells can dramatically affect activity of immune cells, strongly suggesting that EBV contributes to multiple immunosuppressive mechanisms in NPC tissues. Therefore, we plan to extend our molecular study of gene regulation to the functional study investigating immunoregulatory roles of EBV in the tumor microenvironment of NPC.

 

Selected Publications

  • Meichi Hsu, Shih-Yi Wu, Shih-Shin Chang, Ih-Jen Su, Ching-Hwa Tsai, Siao-Jing Lai, Ai-Li Shiau, Kenzo Takada, and Yao Chang* (*co-first author and corresponding author) (2008) Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells. Journal of Virology, 82:3679-3688.
  • Wen-Chuan Hsieh, Yao Chang, Mei-Chi Hsu, Guan-Chung Hsiao, Huai-Chia Chuang, and Ih-Jen Su (2007) Emergence of anti-red blood cell antibodies triggers red cell phagocytosis by activated macrophages in a rabbit model of Epstein-Barr virus-associated hemophagocytic syndrome. American Journal of Pathology, 170:1629-1639.
  • Huai-Chia Chuang, Jong-Ding Lay, Shuang-En Chuang, Wen-Chuan Hsieh, Yao Chang, and Ih-Jen Su (2007) Epstein-Barr Virus (EBV) latent membrane protein-1 down-regulates tumor necrosis factor-a (TNF-a) receptor-1 and confers resistance to TNF-a-induced apoptosis in T cells: implication for the progression to T-cell lymphoma in EBV-associated hemophagocytic syndrome. American Journal of Pathology, 170:1607-1617.
  • Yao Chang, Heng-Huan Lee, Yu-Te Chen, Jean Lu, Shih-Yi Wu, Chaio-Wei Chen, Kenzo Takada, and Ching-Hwa Tsai (2006) Induction of the early growth response-1 gene by Epstein-Barr virus lytic transactivator Zta. Journal of Virology, 80:7748-7755.
  • Huai-Chia Chuang, Jong-Ding Lay, Wen-Chuan Hsieh, Hui-Ching Wang, Yao Chang, Shuang-En Chuang, and Ih-Jen Su (2005) Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood, 106:3090-3096.
  • Yao Chang, Tso-Ching Lee, Jian-Chiuan Li, Ting-Lung Lai, Huey-Huey Chua, Chi-Long Chen, Shin-Lian Doong, Chen-Kung Chou, Tzung-Shiahn Sheen, and Ching-Hwa Tsai (2005) Differential expression of osteoblast-specific factor 2 and polymeric immunoglobulin receptor genes in nasopharyngeal carcinoma. Head & Neck, 27:873-882.
  • Tsuey-Ying Hsu, Yao Chang, Pei-Wen Wang, Mei-Ying Liu, Mei-Ru Chen, Jen-Yang Chen, and Ching-Hwa Tsai (2005) Reactivation of Epstein-Barr virus can be triggered by an Rta protein mutated at the nuclear localization signal. Journal of General Virology, 86:317-322.
  • Yao Chang, Heng-Huan Lee, Shih-Shin Chang, Tsuey-Ying Hsu, Pei-Wen Wang, Yu-Sun Chang, Kenzo Takada, and Ching-Hwa Tsai (2004) Induction of Epstein-Barr virus latent membrane protein 1 by a lytic transactivator Rta. Journal of Virology, 78:13028-13036.
 

 

 


 

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