Zhang Yongliang, Liu Qiuyan, Zhang Minggang, Yu Yizhi, Liu Xia, Cao Xuetao
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
J Immunol. 2009 Mar 15;182(6):3801-8. doi: 10.4049/jimmunol.0801548.
Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer's refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3(+) regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE(2) by activating p38 pathway, and in turn, 3LL cells-derived PGE(2) contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE(2), thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.
Fas/FasL系统因其诱导细胞凋亡的能力而受到广泛研究。然而，越来越多的证据表明，Fas信号也表现出非凋亡功能，如诱导细胞增殖和分化。肺癌是免疫治疗难治的癌症之一，但其潜在机制仍有待充分了解。在本研究中，我们发现Fas过表达不影响3LL细胞的体外生长，但能促进体内肺癌生长。然而，在FasL缺陷（gld）小鼠中未观察到这种促肿瘤作用，在接种了表达结构域阴性Fas的3LL细胞的免疫健全小鼠中也未观察到，这表明Fas信号在促进体内肺癌生长中起关键作用。在接种了过表达Fas的3LL细胞形成的肿瘤中发现了更多的髓源性抑制细胞（MDSC）和Foxp3(+)调节性T细胞，但在接种了表达结构域阴性Fas的3LL细胞形成的肿瘤中未发现。相应地，Fas连接的3LL肺癌细胞在体外能趋化更多的MDSC而不是调节性T细胞。此外，Fas连接通过激活p38途径诱导3LL肺癌细胞产生促炎因子PGE(2)，反过来，3LL细胞衍生的PGE(2)有助于Fas连接诱导的MDSC趋化。此外，体内给予环氧化酶-2抑制剂可显著减少过表达Fas的肿瘤中MDSC的积累。因此，我们的结果表明，Fas信号可通过癌细胞衍生的PGE(2)招募MDSC来促进肺癌生长，从而为炎症在癌症进展和免疫逃逸中的作用提供了新的机制解释。
