Tumor-released Galectin-3, a soluble inhibitory ligand of human NKp30, plays an important role in tumor escaping from NK cell attack [Cell Biology]

October 14th, 2014 by Wang, W., Guo, H., Geng, J., Zheng, X., Wei, H., Sun, R., Tian, Z.

Human Galectin-3, a β-galactoside-binding protein expressed by tumor cells, was reported to act as an immune regulator in anti-tumor T cells; however, its effect on NK cells is elusive. Using a recombinant human NK cell activating receptor NKp30 fusion protein (NKp30-Fc), we found that soluble NKp30-Fc could immunoprecipitate Galectin-3. The direct interaction between NKp30 and Galectin-3 was further confirmed using surface plasmon resonance (SPR) experiments. Because Galectin-3 was mainly released from tumor cells in a soluble form in our study, the binding assay was performed to show that soluble Galectin-3 specifically bound to NK cells and NKp30 on the surface of the NK cells. Functionally, when soluble Galectin-3 was added to the NK-tumor cell co-culture system, the NKp30-mediated, but not NKG2D-mediated, cytolysis and CD107a expression in the NK cells were inhibited, and these phenotypes could be restored by pre-incubation of soluble Galectin-3 with NKp30-Fc fusion protein or the addition of anti-Gal-3 antibody alone. Moreover, genetic downregulation of Galectin-3 (shGal-3) resulted in tumor cells being more sensitive to NK cell lysis, and reversely, Galectin-3-overexpressing HeLa cells (exGal-3) became less sensitive to NK cell killing. The results of these in vitro experiments were supported by studies in shGal-3-HeLa or exGal-3-HeLa xenograft NOD-SCID mice after NK cell adoptive immunotherapy, indicating that Galectin-3 strongly antagonizes human NK cell attack against tumors in vivo. These findings indicate that Galectin-3 may function as an immune regulator to inhibit NK cell function against tumors, thus providing a new therapeutic target for tumor treatment.
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