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

Zhu,Yi; Zhang,Jing-Jing; Liang,Wen-Biao; Zhu,Rong; Wang,Bin; Miao,Yi; Xu,Ze-Kuan

doi:10.3892/or.2014.3016

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

Authors:
- Yi Zhu
- Jing-Jing Zhang
- Wen-Biao Liang
- Rong Zhu
- Bin Wang
- Yi Miao
- Ze-Kuan Xu
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Affiliations: Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Jiangsu Province Blood Center, Nanjing, Jiangsu 210042, P.R. China, Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Nanjing 215006, P.R. China
Published online on: February 10, 2014 https://doi.org/10.3892/or.2014.3016
Pages: 1768-1776

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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.

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