title: Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders.
abstract: Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4(+) Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8(+) T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ouyang
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Evan
authors.initials: E
authors.lastname: O'Donnell
authors.forename: Treeve
authors.initials: T
authors.lastname: Currie
authors.forename: Myriam
authors.initials: M
authors.lastname: Armant
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takeyama
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D037483:Galectin 1 / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000821:virology*; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D037483:Galectin 1; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins