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Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9. Using a novel monoclonal antibody (mAb) (Clone P4D2) that binds the C-terminal carbohydrate recognition domain (CRD) of galectin-9, we demonstrate unique agonistic properties resulting in MM cell apoptosis. Furthermore, the P4D2 mAb reduced tumor-associated macrophages differentiation toward a protumor phenotype. Importantly, these effects exerted by the P4D2 mAb were observed in both human and mouse in vitro experiments and not observed with another antigalectin-9 specific mAb (clone P1D9) that engages the N-terminus CRD of galectin-9. In syngeneic murine models of MM, P4D2 mAb treatment inhibited tumor growth and improved survival, with tumors from P4D2-treated mice exhibited reduced infiltration of tumor-associated M2 macrophages. This was consistent with an increased production of inducible nitric oxide synthase, which is a major enzyme-regulating macrophage inflammatory response to cancer. These data suggest that using an antigalectin 9 mAb with agonistic properties similar to those exerted by galectin-9 may provide a novel multitargeted strategy for the treatment of mesothelioma and possibly other galectin-9 expressing tumors.

Galectins constitute a family of β-galactoside-binding proteins (lectins) that are widely distributed in nature occurring in mammals, sponges, fungi, nematodes, insects and viruses. Galectins are involved in fundamental cellular processes in human skin and other tissues. They exert biological effects of considerable importance through interactions with cytoplasmic and nuclear proteins, as well as with components of cell surface and extracellular matrix. In this paper we summarize current knowledge on the expression of galectins 7 and 9 in normal and diseased human skin and present the future perspectives of the use of these galectins or their antagonists/inhibitors in the diagnosis, prognosis and treatment of cutaneous disorders. [ABSTRACT FROM AUTHOR]

Galectin 9, a ligand of T cell immunoglobulin and mucin domain 3 (TIM-3), and PINCH, an epithelial-to-mesenchymal transition (EMT)-promoting molecule, are expressed at much higher levels in cancerous lesions of clear cell type renal cell carcinoma (RCC) compared to normal renal tissues, and their expression levels are extremely low in normal tissues, except for galectin 9 in the spleen. Galectin 9- and PINCH-derived peptides have previously been shown to induce human leukocyte antigen (HLA)-A*2402-restricted and HLA-A*0201-restricted cytotoxic lymphocytes (CTLs) with specific and highly cytotoxic activities toward RCC cells. The present study aimed to identify the peptides that induced HLA-A*33-restricted CTLs that exhibited specific and highly cytotoxic activities toward RCC cells. Specific CTLs were induced significantly, as shown by cluster of differentiation 107a degranulation stimulated with VMRC-RCW renal carcinoma cells. Therefore, peptide vaccines targeting galectin 9 and PINCH appear to be promising for clinical application. [ABSTRACT FROM AUTHOR]

Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9. Using a novel monoclonal antibody (mAb) (Clone P4D2) that binds the C-terminal carbohydrate recognition domain (CRD) of galectin-9, we demonstrate unique agonistic properties resulting in MM cell apoptosis. Furthermore, the P4D2 mAb reduced tumor-associated macrophages differentiation toward a protumor phenotype. Importantly, these effects exerted by the P4D2 mAb were observed in both human and mouse in vitro experiments and not observed with another antigalectin-9 specific mAb (clone P1D9) that engages the N-terminus CRD of galectin-9. In syngeneic murine models of MM, P4D2 mAb treatment inhibited tumor growth and improved survival, with tumors from P4D2-treated mice exhibited reduced infiltration of tumor-associated M2 macrophages. This was consistent with an increased production of inducible nitric oxide synthase, which is a major enzyme-regulating macrophage inflammatory response to cancer. These data suggest that using an antigalectin 9 mAb with agonistic properties similar to those exerted by galectin-9 may provide a novel multitargeted strategy for the treatment of mesothelioma and possibly other galectin-9 expressing tumors. [ABSTRACT FROM AUTHOR]