High expression of Galectin‐1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer

Abstract

Galectin-1 is implicated in making tumor cells immune privileged, in part by regulating the survival of infiltrating T cells. Galectin-1 is strongly expressed in activated pancreatic stellate cells (PSCs); however, whether this is linked to tumor cell immune escape in pancreatic cancer is unknown. Galectin-1 was knocked down in PSCs isolated from pancreatic tissues using small interfering RNA (siRNA), or overexpressed using recombinant lentiviruses, and the PSCs were cocultured with T cells. CD31 , CD4 1 and CD8 1 T cell apoptosis was detected by flow cytometry; T cell IL-2, IL-4, IL-5 and INF-c production levels were quantified using ELISA. Immunohistochemical analysis showed increased numbers of PSCs expressed Galectin-1 (p < 0.01) and pancreatic cancers had increased CD3 1 T cell densities (p < 0.01) compared to normal pancreas or chronic pancreatitis samples. In coculture experiments, PSCs that overexpressed Galectin-1 induced apoptosis of CD4 1 T cells (p < 0.01) and 05). Supernatants from T cells cocultured with PSCs that overexpressedGalectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-c, p < 0.01). However, the knockdown of PSC Galectin-1 had the opposite effect on Th1 and Th2 cytokine secretion. Our study suggests that the overexpression of Galectin-1 in PSCs induced T cell apoptosis and Th2 cytokine secretion, which may regulate PSC-dependent immunoprivilege in the pancreatic cancer microenvironment. Galectin-1 may provide a novel candidate target for pancreatic cancer immunotherapy.Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, which is resistant to currently available systemic therapies. PDAC has one of the worst prognoses of all human cancers with incidence rates nearly equal to mortality rates. 1 There is evidence that excessive desmoplasia play a crucial role in the aggressive behavior of pancreatic cancer, 2 which impedes effective systemic treatments on a molecular level. Pancreatic stellate cells (PSCs) are stellate-shaped mesenchymal pancreatic cells, which have been identified as important regulators of desmoplasia in PDAC. 3In their quiescent state, PSCs can be identified by the presence of vitamin A-containing lipid droplets in the cytoplasm and the expression of desmin and glial-fibrillary-acidic protein (GFAP). 4 In response to pancreatic damage or stress, PSC are transformed into an activated myofibroblast-like phenotype. Activated PSCs express a-smooth muscle actin (a-SMA), and synthesize excessive amounts of ECM proteins, including Collagen I and III, fibronectin and matrix-degrading enzymes such as MMPs.5-7 Activated PSCs have a variety of cell functions and can promote the proliferation, migration, invasion and metastasis of pancreatic cancer cells; 1,8,9 however, the factors that PSCs secrete to advance pancreatic cancer progression remain largely unknown.Galectin-1, a member of the galectin family of b-galactosidebinding proteins, is a homodimer of 14-kDa subunits pos...

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

“…Research from our laboratory has recognized an essential role for Gal1 as an immunoevasive mechanism in human and mouse melanoma (9). These observations were further confirmed in mouse lung adenocarcinoma (10,11), and in human cancers including Hodgkin lymphoma (12,13), neuroblastoma (14), head and neck squamous cell carcinoma (15), pancreatic carcinoma (16), glioma (17), and T-cell lymphoma (18), suggesting that targeting the Gal1-glycan axis might contribute to overcome immunosuppression and potentiate immunotherapeutic approaches. Interestingly, Gal1 was identified as a tumor-associated protein capable of delineating the metastatic potential of human breast carcinoma (19,20).…”

Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

“…Another PDAC-associated adhesion molecule, an ICAM-1 receptor α L β 2 integrin (also known as LFA-1 or CD11a/CD18), regulates CD8 + T cell recruitment: only its knockout results in a marked impairment of CD8 + T cell infiltration in experimental pancreatic tumors in mice, probably because its lack of expression impairs T cells activation and differentiation [112]. Overexpression and secretion by activated PSCs of β-galactoside-binding protein Galectin-1 (Gal-1), another molecule that mediates immunosuppression in PDAC by targeting T cell, increases Th2 and decreases Th1 cytokines, inducing CD4 + and CD8 + T cell apoptosis [113].…”

“…Genetic ablation of Gal-1 in a murine PDAC model dampened tumor progression by inhibiting proliferation, angiogenesis and the desmoplasic reaction, and also by triggering a tumor-associated immune response, thus leading toa 20% increase in relative lifespan [145]. However, Gal-1 overexpression is found on the stromal tissues of long term pancreatic cancer survivors [113], indicating that the prognostic significance of Gal-1 expression is not entirely clear. Blocking molecules for Gal-1 is a potential strategy for cancer treatment.…”

Galectin-1 as a therapeutic target in pancreatic cancer: the tumor stroma in the spotlight

“…In vitro experiments have shown that Gal1 is involved in pancreatic stellate cell activation [10,11] , contributing to the immune escape [12] and favoring tumor invasion and migration [13,14] . Although in humans, Gal1 tumor levels faithfully correlate with PDA stage [15] and patient survival [16,17] , previous studies were only descriptive and did not provide any insights about the mechanism of the in vivo Gal1 role during pancreatic tumor progression.…”