Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy
Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy
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DOI：
10.4049/jimmunol.170.12.6338
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发表时间：
2003-06-15
影响因子：
4.4
通讯作者：
Hodge, JW
中科院分区：
文献类型：
--
作者：
Chakraborty, M;Abrams, SI;Hodge, JW
CD 8（+）CTL在肿瘤的主动和被动免疫治疗中发挥重要作用。尽管如此，抗肿瘤细胞毒性T细胞反应的成功可以通过其他治疗方式来改善。放射疗法，这在治疗肿瘤性疾病中具有长期的用途，已被发现在癌细胞中诱导影响Fas基因表达的独特生物学改变，其因此可能影响CTL的总体裂解效率。在这里，在小鼠腺癌细胞模型中，我们研究了这些肿瘤细胞暴露于亚致死剂量的辐射是否1）增强Fas表达，导致体外通过Fas依赖性机制更有效的CTL杀伤;和2）通过过继转移这些Ag特异性CTL提高体内抗肿瘤活性。在体外用辐射（20戈伊）处理癌胚性表达Ag的MC 38腺癌细胞在分子、表型和功能水平上增强Fas表达。此外，辐射敏化这些目标Ag特异性CTL杀伤通过Fas/Fas配体途径。我们研究了局部照射s.c.生长肿瘤对CTL过继免疫疗法的效率的影响。基于免疫组织化学，放射线照射引起这些肿瘤细胞原位Fas上调。此外，局部照射的肿瘤显着增强肿瘤排斥这些癌胚抗原特异性CTL。总体而言，这些结果首次表明：1）通过照射调节肿瘤细胞中Fas通路在其对Ag特异性CTL的敏化中起重要作用; 2）肿瘤靶向照射和CTL的组合方案促进体内更有效的抗肿瘤应答，这可能对免疫治疗和放射治疗的组合具有意义。
CD8(+) CTL play important roles against malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities. Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse adenocarcinoma cell model, we examined whether exposure of these tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the tumor significantly potentiated tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of immunotherapy and radiation therapy.