Immune response modulation by Galectin-1 in a transgenic model of neuroblastoma

Abstract

Galectin-1 (Gal-1) has been described to promote tumor growth by inducing angiogenesis and to contribute to tumor immune escape by promoting apoptosis of activated T cells. We had previously identified upregulation of Gal-1 in preclinical models of aggressive neuroblastoma (NB), a solid tumor of childhood. However, the clinical and biological relevance of Gal-1 in this tumor entity is unclear. Here, the effect of Gal-1 on the immune system and tumorigenesis was assessed using modulation of Gal-1 expression in immune effector cells and in a transgenic NB model, designated TH-MYCN. The fraction of CD4(+) T cells was decreased in tumor-bearing TH-MYCN mice compared to tumor-free littermates, while both CD4(+) T cells as well as CD8(+) T cells were less activated, compatible with a reduced immune response in tumor-bearing mice. Tumor incidence was not significantly altered by decreasing Gal-1/LGALS1 gene dosage in TH-MYCN mice, but TH-MYCN/Gal-1(-/-) double transgenic mice displayed impaired tumor angiogenesis, splenomegaly, and impaired T cell tumor-infiltration with no differences in T cell activation and apoptosis rate. Additionally, a lower migratory capacity of Gal-1 deficient CD4(+) T cells toward tumor cells was observed in vitro. Transplantation of TH-MYCN-derived tumor cells into syngeneic mice resulted in significantly reduced tumor growth and elevated immune cell infiltration when Gal-1 was downregulated by shRNA. We therefore conclude that T cell-derived Gal-1 mediates T cell tumor-infiltration, whereas NB-derived Gal-1 promotes tumor growth. This opposing effect of Gal-1 in NB should be considered in therapeutic targeting strategies, as currently being developed for other tumor entities.

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance

“…Most studies evaluating the immune effects of Gal1 in cancer have focused on its role in causing T cell apoptosis (19). However, the relevance of Gal1 in the tumor microenvironment has been questioned, because physiological concentrations of Gal1 are unlikely to reach the concentrations necessary to induce apoptosis (20,21). Because Gal1 shows a strong inverse correlation with T cell levels and a direct relationship with tumor progression in HNCs, we decided to evaluate whether Gal1 could be a significant player in causing T cell exclusion and immunotherapy resistance.…”

Both serum and tissue Galectin‐1 levels are associated with adverse clinical features in neuroblastoma

“…Galectin‐1 participates in various physiologic processes including neural stem cell growth, hematopoietic differentiation, and muscle differentiation . Recent evidence indicates that Galectin‐1 contributes to various biological events associated with tumor progression, including tumor immune‐escape, proliferation, angiogenesis, cell cycle progression, apoptosis, cell adhesion, and migration …”

“…[20][21][22] Galectin-1 partic-ipates in various physiologic processes including neural stem cell growth, hematopoietic differentiation, and muscle differentiation. 23 Recent evidence indicates that Galectin-1 contributes to various biological events associated with tumor progression, including tumor immune-escape, 17,24 proliferation, 16 angiogenesis, 25 cell cycle progression, apoptosis, cell adhesion, and migration. 23,26 Despite increased Galectin-1 expression in various malignant tumors, very little has been reported regarding the diagnostic and prognostic values of Galectin-1 in neuroblastoma.…”

“…Previous immunohistochemical analyses found increased Galectin‐1 expression in patients with advanced‐stage neuroblastoma and differentiating neuroblastoma tumors . Neuroblastoma‐derived Galectin‐1 could promote tumor growth, and silencing Galectin‐1 caused a reduction of primary tumor growth in a subcutaneous xenotransplantation tumor model …”

“…14,15 Previous immunohistochemical analyses found increased Galectin-1 expression in patients with advanced-stage neuroblastoma and differentiating neuroblastoma tumors. 16 Neuroblastoma-derived Galectin-1 could promote tumor growth, 17 and silencing Galectin-1 caused a reduction of primary tumor growth in a subcutaneous xenotransplantation tumor model. 18 Due to the fact that Galectin-1 is present and functions in both the intracellular and extracellular domains, whether serum sGalectin-1 could affect the progression of neuroblastoma and if there is a connection between tissue Galectin-1 expression and sGalectin-1 remains unknown.…”