The AP1-dependent secretion of galectin-1 by Reed-Sternberg cells fosters immune privilege in classical Hodgkin lymphoma

Proc. Natl. Acad. Sci. USA 104(32):13134-13139, 2007. Published: 2007.08.06

Przemyslaw Juszczynski, Jing Ouyang, Stefano Monti, Scott J. Rodig, Kunihiko Takeyama, Jeremy Abramson, Wen Chen, Jeffery L. Kutok, Gabriel A. Rabinovich, and Margaret A. Shipp

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Abstract

Classical Hodgkin lymphomas (cHLs) contain small numbers of neoplastic Reed-Sternberg (RS) cells within an extensive inflammatory infiltrate that includes abundant T helper (Th)-2 and T regulatory (Treg) cells. The skewed nature of the T cell infiltrate and the lack of an effective host antitumor immune response suggest that RS cells use potent mechanisms to evade immune attack. In a screen for T cell-inhibitory molecules in cHL, we found that RS cells selectively overexpressed the immunoregulatory glycan-binding protein, galectin-1 (Gal1), through an AP1-dependent enhancer. In cocultures of activated T cells and Hodgkin cell lines, RNAi-mediated blockade of RS cell Gal1 increased T cell viability and restored the Th1/Th2 balance. In contrast, Gal1 treatment of activated T cells favored the secretion of Th2 cytokines and the expansion of CD4+CD25high FOXP3+ Treg cells. These data directly implicate RS cell Gal1 in the development and maintenance of an immunosuppressive Th2/Treg-skewed microenvironment in cHL and provide the molecular basis for selective Gal1 expression in RS cells. Thus, Gal1 represents a potential therapeutic target for restoring immune surveillance in cHL.

Keywords: Th2 Treg c-Jun immunomodulation microenvironment