Pancreatic cancer counterattack: MUC4 mediates Fas-independent apoptosis of antigen-specific cytotoxic T lymphocyte

Abstract

Tumor-associated MUC4 mucin has considerable potential as an immunotherapy target for pancreatic cancer. In previous studies, we developed dendritic cell (DC) vaccines which elicited MUC4 antigen-specific cytotoxic T lymphocyte (MS-CTL) response against tumor cells in vitro. Due to the observation that MS-CTL apoptotic rate increased significantly when co-cultured with MUC4+ tumor cells compared with T2 cells, we investigated whether high expression levels of MUC4 in pancreatic cancer cells would have an effect on the significant increase of apoptosis rate of MS-CTLs. First, the adverse influence of regulatory T cells (Tregs) was eliminated by CD8+ T lymphocyte sorting before the induction of MS-CTLs. Then, we constructed clonal MUC4-knockdown HPAC pancreatic cancer sublines with different MUC4 expression for co-incubation system. By utilizing appropriate control to rule out the possible apoptosis-induced pathway of intrinsic activated cell-autonomous death (ACAD) and analogous antigen-dependent apoptosis of CTL (ADAC) in our study system, further analysis of the effect of MUC4 membrane-expression, supernatants and blockade of CTL surface Fas receptor on MS-CTL apoptosis was carried out. The results demonstrated that the level of MUC4 membrane expression strongly positively correlated with MS-CTL apoptosis and the influence of supernatants and Fas-blockade did not significantly correlate with MS-CTL apoptosis. This evidence suggested that there may be a novel counterattack pathway of pancreatic cancer cells, which is a MUC4-mediated, cell contact-dependent and Fas-independent process, to induce CTL apoptosis. Therefore, further exploration and understanding of the potential counterattack mechanisms is beneficial to enhance the efficacy of MUC4 specific tumor vaccines.

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

“…This was attributed to the large molecular size of Muc4 that prevented the interaction of cancer cells with LAK cells by steric hindrance and resulted in masking of cancer-associated epitopes, thereby facilitating immune evasion [44]. In pancreatic cancer cells, MUC4 has been implicated in promoting the apoptosis of MUC4-specific cytotoxic T-lymphocytes (CTL), in a cell contact dependent and Fas ligand independent manner [20]. This is an interesting observation that may explain the suboptimal cytotoxic response of effector T cells, but in-depth investigation is required to further validate the role of MUC4 in mediating tumor cell-cytotoxic T-lymphocyte (CTL) interactions.…”

“…These diverse functions of MUC4 have been attributed to its ability to interact with multiple proteins including epidermal growth factor receptor (EGFR) family members [18], extracellular matrix components like fibulin-2 [19], and circulating, metastasis-promoting factors like soluble galectin-3 [13]. Furthermore, the expression of MUC4 on PDAC cells has been demonstrated to compromise the immune effector response by facilitating apoptosis of antigen-specific cytotoxic T cells [20]. Due to its differential overexpression and functional involvement in various aspects of PDAC pathobiology, MUC4 has emerged as a potential therapeutic target for directly abrogating MUC4-mediated progression and for enhancing the efficacy of chemotherapeutic and immunotherapeutic regimens.…”

Decoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells

“…Evidence for this hypothesis has been reported in renal, gastric and colon cancer [8]. However, some tumor cells, including pancreatic cancer cells and melanoma cells, do not express FasL [9,10].…”

NIDO, AMOP and vWD domains of MUC4 play synergic role in MUC4 mediated signaling

“…The levels of MUC4 expression rise consistently with the PanIN-PDAC progression model, and correlate significantly with poor prognosis of PDAC [7, 9, 10]. As our and other studies in the literature have reported, pancreatic cancer cells can exploit the multi-functions of MUC4 to trigger malignant activities including proliferation [11, 12, 14, 16], resistance to apoptosis [14, 16], motility [16], invasiveness & neural invasion [15, 16, 17], angiogenesis [12, 16], metastasis [11–13, 15, 16], supressing immune [18], and chemoresistance [19–21]. Thus MUC4 is an important potential target to overcome pancreatic cancer.…”