Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion.
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.
Huang
Xiaoyuan
X
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
Bai
Xiangyang
X
Cao
Yang
Y
Wu
Jingyi
J
Huang
Mei
M
Tang
Duozhuang
D
Tao
Si
S
Zhu
Tao
T
Liu
Yanling
Y
Yang
Yang
Y
Zhou
Xiaoxi
X
Zhao
Yanxia
Y
Wu
Mingfu
M
Wei
Juncheng
J
Wang
Daowen
D
Xu
Gang
G
Wang
Shixuan
S
Ma
Ding
D
Zhou
Jianfeng
J
D015703:Antigens, CD / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018450:Disease Progression; D004727:Endothelium / Q000473:pathology* / Q000503:physiopathology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods; D008198:Lymph Nodes / Q000473:pathology / Q000601:surgery; D008213:Lymphocyte Activation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000601:surgery; D008565:Membrane Proteins / Q000235:genetics*; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D015703:Antigens, CD; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A