title: 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.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Huang
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Bai
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Jingyi
authors.initials: J
authors.lastname: Wu
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.forename: Duozhuang
authors.initials: D
authors.lastname: Tang
authors.forename: Si
authors.initials: S
authors.lastname: Tao
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhou
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mingfu
authors.initials: M
authors.lastname: Wu
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.forename: Daowen
authors.initials: D
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: 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
chemical_list: 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