title: Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma.
abstract: Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin-domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.
authors.affiliation: aMayo Graduate School bDivision of Hematology cDivision of Oncology dHealth Sciences Research, Mayo Clinic, Rochester eDepartment of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Elizabeth Ann L
authors.initials: EA
authors.lastname: Enninga
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Nevala
authors.forename: Shernan G
authors.initials: SG
authors.lastname: Holtan
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Leontovich
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
mesh_terms: D002454:Cell Differentiation; D005260:Female; D037161:Galectins / Q000276:immunology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D018418:Th2 Cells
chemical_list: D037161:Galectins