Tumor-released Galectin-3, a soluble inhibitory ligand of human NKp30, plays an
important role in tumor escape from NK cell attack
#MMPMID25315772
Wang W
; Guo H
; Geng J
; Zheng X
; Wei H
; Sun R
; Tian Z
J Biol Chem
2014[Nov]; 289
(48
): 33311-9
PMID25315772
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Human Galectin-3 (Gal-3), a ?-galactoside-binding protein expressed by tumor
cells, has been reported to act as an immune regulator in antitumor T cells.
However, its effect on natural killer (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 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
coculture 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 preincubation of soluble Galectin-3 with NKp30-Fc fusion protein or
the addition of anti-Gal-3 antibody alone. Moreover, genetic down-regulation 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 non-obese
diabetic/severe combined immunodeficiency 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,
therefore providing a new therapeutic target for tumor treatment.
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