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

Jing Ouyang, Przemyslaw Juszczynski, Scott J. Rodig, Michael R. Green, Evan O'Donnell, Treeve Currie, Myriam Armant, Kunihiko Takeyama, Stefano Monti, Gabriel A. Rabinovich, Jerome Ritz, Jeffery L. Kutok, Margaret A. Shipp

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51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4315-4322
Number of pages8
JournalBlood
Volume117
Issue number16
DOIs
StatePublished - Apr 21 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ouyang, J., Juszczynski, P., Rodig, S. J., Green, M. R., O'Donnell, E., Currie, T., Armant, M., Takeyama, K., Monti, S., Rabinovich, G. A., Ritz, J., Kutok, J. L., & Shipp, M. A. (2011). Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders. Blood, 117(16), 4315-4322. https://doi.org/10.1182/blood-2010-11-320481