The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Przemyslaw
P
Juszczynski
Jing
J
Ouyang
Stefano
S
Monti
Scott J
SJ
Rodig
Kunihiko
K
Takeyama
Jeremy
J
Abramson
Wen
W
Chen
Jeffery L
JL
Kutok
Gabriel A
GA
Rabinovich
Margaret A
MA
Shipp
D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000502:physiology; D037483:Galectin 1 / Q000502:physiology*; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016539:Reed-Sternberg Cells / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000502:physiology*
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037483:Galectin 1; C445499:LGALS1 protein, human; D018808:Transcription Factor AP-1