Anticancer effects of adenovirus-mediated calreticulin and melanoma-associated antigen 3 expression on non-small cell lung cancer cells

作者：Liu, Xinli; Sun, Nan; Dong, Yinan; Li, Jijia; Liu, Yang; Ren, Yi; Yang, Chengliang; Zhang, Liang; Zhou, Yang; Tong, Zhuang; Ding, Jianqiao; Zhao, Xiang; Liu, Yu; He, Rong; Xu, Ke; Wu, Yongkai; Huang, Yanfeng; Wang, Hui; Tao, Xiujuan; Liu, Yongyu

来源：International Immunopharmacology, 2015, 25(2): 416-424.

DOI：10.1016/j.intimp.2015.02.017

• Calreticulin
• Melanoma antigen gene-A3
• Non-small cell lung cancer
• Dendritic cells
• CD8+T cells

Non-small cell lung cancer (NSCLC) is highly prevalent and needs novel therapies. Melanoma-associated antigen 3 (MAGE-A3) is a lung cancer antigen and calreticulin (CALR) can modulate immune responses. Our previous study has shown that up-regulated MAGE-A3 and CALR expression inhibits the proliferation and invasion of glioma cells. In this study, we examined the effect of adenovirus (Ad)-mediated MAGE-A3 and/or CALR expression on the proliferation, invasion, and apoptosis of human NSCLC cells and on the vascular tube formation of human endothelial cells as well as on dendritic cell (DC) activation and induced CD8(+) cytotoxic T lymphocyte (CTL) activity in vitro. We found that low levels of CALR and MAGE-A3 were expressed by A549 cells, but only very low CALR was expressed by DC. Up-regulated CALR and MAGE-A3 expression by infection with Ad-CALR/MAGE-A3 significantly inhibited the proliferation and invasion, but promoted the apoptosis of A549 cells. Up-regulated CALR and MAGE-A3 expression significantly inhibited cyclin D1 expression and the ART, ERK1/2 and NF-kappa B expression and phosphorylation in A549 cells. Up-regulated CALR expression inhibited the tube formation in human endothelial cells. Up-regulated CALR and MAGE-A3 expression synergistically enhanced classical DC activation by enhancing IL-12, but reducing IL-10 secretion. Furthermore, CTLs induced by up-regulated CALR and MAGE-A3 expressing DCs synergistically triggered A549 cell apoptosis, which was abrogated by treatment with anti-HLA I, but not anti-HLA II antibodies. Moreover, CTLs induced by CALR and MAGE-A3-expressing DCs had a higher frequency of A549-specific IFN-gamma-secreting T cells. Our data indicated that up-regulated CALR and MAGE-A3 expression inhibited the carcinogenesis of NSCLC by modulating the ART, ERR MAPK and NF-kappa B signaling and enhanced classical DC activation and MAGE-A3-specific CTL cytotoxicity. Therefore, our findings may provide new insights in understanding the role of CALR in modulating antigen-specific T cell immunity and may aid in the design of new therapies for NSCLC.

• 出版日期2015-4
• 单位辽宁省肿瘤医院