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

doi:10.1073/pnas.0706017104

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

*Department of Medical Oncology, Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115;
^†Broad Institute, Cambridge Center, Cambridge, MA 02142;
^‡Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115; and
^§Institute of Biology and Experimental Medicine, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Vuelta de Obligado 2490 and Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, C1428ADN, Buenos Aires, Argentina

Communicated by Klaus Rajewsky, Harvard Medical School, Boston, MA, June 26, 2007 (received for review April 23, 2007)

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 (T_reg) 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⁺CD25^high FOXP3⁺ T_reg cells. These data directly implicate RS cell Gal1 in the development and maintenance of an immunosuppressive Th2/T_reg-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.

Footnotes

^¶To whom correspondence should be addressed. E-mail: margaret_shipp{at}dfci.harvard.edu
Author contributions: P.J. and J.O. contributed equally to this work; P.J., J.O., S.M., J.A., J.L.K., G.A.R., and M.A.S. designed research; P.J., J.O., S.M., S.J.R., K.T., W.C., and J.L.K. performed research; G.A.R. contributed new reagents/analytic tools; P.J., J.O., S.M., K.T., and J.L.K., G.A.R., and M.A.S. analyzed data; and P.J., J.O., G.A.R., and M.A.S. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706017104/DC1.
Abbreviations:

AP1,

activator protein 1;

cHL,

classical Hodgkin lymphoma;

DLBCL,

diffuse large B cell lymphoma;

DN,

dominant-negative;

Gal1,

galectin-1;

MLBCL,

mediastinal large B cell lymphoma;

PE,

phycoerythrin;

QPCR,

quantitative PCR;

rGal1,

recombinant Gal1;

RS cell,

Reed–Sternberg cell;

SCR,

scrambled control shRNA;

shRNA,

short hairpin RNA;

Treg,

regulatory T cell;

TDG,

thiodigalactoside;

Th cell,

T helper cell.
Freely available online through the PNAS open access option.