Abstract
Galectins are one of the critical players in the tumor microenvironment–tumor crosstalk and the regulation of local immunity. Galectin-9 has been in the limelight in tumor immunology. Galectin-9 possesses its multiplex biological functions both extracellularly and intracellularly, plays a pivotal role in the modulation of adaptive and innate immunity, and induces immune tolerance. NK-92MI cell lines against different malignancies were extensively studied, and recently published trials used genetically chimeric antigen receptor-transfected NK-92MI cells in tumor immunotherapy. Besides the intensive research in tumor immunotherapy, limited information is available on their immune-checkpoint expression and the impact of checkpoint ligands on their effector functions. To uncover the therapeutic potential of modulating Galectin-9-related immunological pathways in NK-cell-based therapy, we investigated the dose-dependent effect of soluble Galectin-9 on the TIM-3 checkpoint receptor and NKG2D, CD69, FasL, and perforin expression of NK-92MI cells. We also examined how their cytotoxicity and cytokine production was altered after Gal-9 treatment and in the presence of different serum supplements using flow cytometric analysis. Our study provides evidence that the Galectin-9/TIM-3 pathway plays an important role in the regulation of NK cell function, and about the modulatory role of Galectin-9 on the cytotoxicity and cytokine production of NK-92MI cells in the presence of different serum supplements. We hope that our results will aid the development of novel NK-cell-based strategies that target Galectin-9/TIM-3 checkpoint in tumors resistant to T-cell-based immunotherapy.
Highlights
According to data from the World Health Organization (WHO) and the latest update from the International Agency for Research on Cancer (IARC) [1], cancer is the second leading cause of death globally, with an estimated 18.1 million cases and 9.6 million cancer deaths
Investigating the T-cell immunoglobulin and mucin domain 3 (TIM-3) receptor expression by Natural killer (NK)-92MI cells cultured in the presence of fetal calf serum (FCS) or AB serum (ABS) additive alone, a statistical difference was not observed in either case
Our data suggest that the expression of the TIM-3 immune checkpoint receptor can be induced on NK-92MI cells by recombinant Gal-9 treatment, and the elevated level of TIM-3, CD69, and NKG2D-activating receptors may mark a dose-dependent activation of these cells, which is strongly masked in the presence of FCS-containing media, but is unmasked when 10% ABS is applied as a culture supplement (Figure 6)
Summary
According to data from the World Health Organization (WHO) and the latest update from the International Agency for Research on Cancer (IARC) [1], cancer is the second leading cause of death globally, with an estimated 18.1 million cases and 9.6 million cancer deaths This number is predicted to increase up to 29.4 million cases by 2040. Tumor immunotherapy has become a novel, promising therapeutic alternative for cancers. As this treatment regimen is highly effective, less toxic, more tolerable, and provides numerous benefits, it has become one of the first choices against many malignant neoplasms [2].
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