Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion.

Abstract

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4(+) T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3(+) ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4(+) T lymphocytes through the activation of the interleukin-6-STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3-expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4(+) T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

• Authors: Xiaoyuan Huang, Xiangyang Bai, Yang Cao, Jingyi Wu, Mei Huang, Duozhuang Tang, Si Tao, Tao Zhu, Yanling Liu, Yang Yang, Xiaoxi Zhou, Yanxia Zhao, Mingfu Wu, Juncheng Wei, Daowen Wang, Gang Xu, Shixuan Wang, Ding Ma, Jianfeng Zhou
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 207 Issue 3 Pg. 505-20 (Mar 15 2010) ISSN: 1540-9538 [Electronic] United States
• PMID: 20176801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• Membrane Proteins
• RNA, Messenger
• Vascular Endothelial Growth Factor A

Topics

• Antigens, CD (genetics)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Disease Progression
• Endothelium (pathology, physiopathology)
• Hepatitis A Virus Cellular Receptor 2
• Humans
• Immune Tolerance
• Immunosuppression Therapy
• Immunotherapy (methods)
• Lymph Nodes (pathology, surgery)
• Lymphocyte Activation
• Lymphoma, Large B-Cell, Diffuse (genetics, immunology, pathology, surgery)
• Membrane Proteins (genetics)
• Neovascularization, Pathologic
• RNA, Messenger (genetics)
• T-Lymphocytes (immunology)
• Transcription, Genetic (immunology)
• Vascular Endothelial Growth Factor A (genetics)