Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders

Authors
Ouyang, Ying; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R.; O´ Donnell, Evan; Currie, Treeve; Armant, Myriam; Takeyama, Kunihiko; Monti, Stefano; Rabinovich, Gabriel Adrian; Ritz, Jerome; Kutok, Jeffery L.; Shipp, Margaret A.
Publication Year
2011
Language
English
Format
article
Status
Published version
Description
Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven 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 Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding 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.
Fil: Ouyang, Ying. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Juszczynski, Przemyslaw. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Rodig, Scott J.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Green, Michael R.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: O´ Donnell, Evan. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Currie, Treeve. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Armant, Myriam. Immune Disease Institute/Harvard Medical School. Center for Human Cell Therapy; Estados Unidos
Fil: Takeyama, Kunihiko. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Monti, Stefano. Broad Institute; Estados Unidos
Fil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Ritz, Jerome. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Kutok, Jeffery L.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Subject
EPSTEIN BARR-VIRUS
LYMPHOPROLIFERATIVE DISORDERS
GALECTIN-1
TRANSPLANTATION
Bioquímica y Biología Molecular
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/10661