title: Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression.
abstract: Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Weng Tong
authors.initials: WT
authors.lastname: Ho
authors.forename: Wan Lu
authors.initials: WL
authors.lastname: Pang
authors.forename: Siew Meng
authors.initials: SM
authors.lastname: Chong
authors.forename: Antonio
authors.initials: A
authors.lastname: Castella
authors.forename: Suhail
authors.initials: S
authors.lastname: Al-Salam
authors.forename: Teng Ee
authors.initials: TE
authors.lastname: Tan
authors.forename: Mei Chung
authors.initials: MC
authors.lastname: Moh
authors.forename: Liang Kai
authors.initials: LK
authors.lastname: Koh
authors.forename: Shu Uin
authors.initials: SU
authors.lastname: Gan
authors.forename: Cheong Kin
authors.initials: CK
authors.lastname: Cheng
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwarz
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism; D045744:Cell Line, Tumor; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016539:Reed-Sternberg Cells / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D053330:4-1BB Ligand; C505974:TNFSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9