Apoptosis and anergy of T cell induced by pancreatic stellate cells-derived galectin-1 in pancreatic cancer

Abstract

Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

“…Caspase-3 is the effector molecule in the apoptotic cascade signaling pathway and is the executive protein of apoptosis (22). As a DNA damage repair molecule, PARP is degraded by caspase-3 and other cysteine proteinases during apoptosis, and its degradation is regarded as an early molecular sign of apoptosis (23). In the present study, it was also identified that down-expression of PARP-1 (via olaparib) significantly decreased the cellular viability of PanC-1 cells, increased p53 protein expression, decreased expression of pro-caspase-3, increased caspase-3 activity and suppressed Bcl-2 protein expression following the inhibition of ATM activity.…”

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

“…The chemokine ligand/receptor has been demonstrated to be a strong chemoattractant for lymphocytes [34]. PSCs also induce T cell apoptosis and anergy by expressing galectin-1 [35]. PSCs may crosstalk with TAMs in PanIN, and these cell populations activate each other by secreting various soluble factors.…”

Kras and Tumor Immunity: Friend or Foe?

“…In addition to the plethora of cytokines and chemokines that are common to aPSCs and Kras-mutant tumor cells, aPSCs secrete a number of unique factors that independently contribute to the immune contexture of PDAC. For example, galectin 1 was found to be a principal mediator of T-cell suppression in PanINs and PDAC and is uniquely expressed by aPSCs (Tang et al 2012(Tang et al , 2015. Zambirinis and colleagues (2015) showed that CCL3 secretion by aPSCs was required for the recruitment of Treg cells in KPC mice.…”