Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction
Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction
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DOI：
10.1038/sj.gt.3302401
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发表时间：
2005-05-01
期刊：
影响因子：
5.1
通讯作者：
Imawari, M
中科院分区：
文献类型：
--
作者：
Eguchi, J;Hiroishi, K;Imawari, M
为了探讨白细胞介素(IL)-4治疗的抗肿瘤机制，我们建立了过表达IL-4的MC38小鼠结直肠癌细胞系（MC38- il4）。作为一种针对已建立肿瘤的治疗方法，在注射野生型（MC38-WT）细胞7天后，对侧接种MC38-IL4细胞，可显著降低野生型肿瘤的生长（P = 0.030）。免疫组化分析显示mc38 - il4接种小鼠的野生型肿瘤有大量粒细胞浸润。将MC38-IL4细胞注射到白细胞减少的小鼠体内，证实了粒细胞参与了il -4相关的原发性抗肿瘤作用。mc38 - il - 4在白细胞减少的小鼠中接种MC38-WT，表明T细胞参与了抗肿瘤作用。为了研究肿瘤特异性反应，我们在体外用MC38-IL4细胞刺激mc38免疫小鼠的脾细胞，导致mc38特异性裂解（57.5 +/- 7.2%，效应靶比= 20）。MC38- il4联合过表达干扰素(IFN)- α的MC38细胞（MC38-IFN α）治疗已建立的野生型肿瘤可显著降低野生型肿瘤的生长（P = 0.009）。与单独注射MC38-IL4相比，同时注射MC38-IL4和- IFN α的小鼠脾细胞在体外产生的IFN- γ大大增加，而IL-10的产生没有增加。因此，粒细胞与IL-4治疗的早期抗肿瘤作用有关。随后，IL-4诱导持久的肿瘤特异性免疫反应。IL-4似乎促进t -辅助性1型抗肿瘤免疫反应，该反应与ifn - α合作增强。
To investigate antitumor mechanisms in interleukin (IL)-4 therapy, we established an IL-4-overexpressing MC38 murine colorectal cancer cell line (MC38-IL4). As a therapy against established tumors, MC38-IL4 cells were inoculated contralaterally 7 days after wild-type (MC38-WT) cells had been injected, significantly reducing growth of wild-type tumors ( P = 0.030). Immunohistochemical analysis showed numerous granulocytes infiltrating wild-type tumors of MC38-IL4-inoculated mice. Injection of MC38-IL4 cells in leukocyte-depleted mice confirmed that granulocytes were involved in IL-4-related primary antitumor effects. Inoculation of MC38-WT in leukocyte-depleted mice initially injected with MC38-IL4 suggested that T cells contributed to the antitumor effects. To investigate tumor-specific responses, we stimulated splenocytes of MC38-immune mice with MC38-IL4 cells in vitro, resulting in MC38-specific lysis (57.5 +/- 7.2%, effector to target ratio = 20). Treatment of established wild-type tumors with MC38-IL4 in combination with interferon (IFN)-alpha- overexpressing MC38 cells (MC38-IFN alpha) significantly reduced the growth of wild-type tumors ( P = 0.009). In vitro IFN-gamma production by splenocytes from mice injected with both MC38-IL4 and - IFN alpha was greatly enhanced in comparison with MC38-IL4 alone, while IL-10 production was not increased. Thus, granulocytes concern early antitumor effects of IL-4 therapy. Subsequently, IL-4 induces long-lasting, tumor-specific immune responses. IL-4 appears to promote a T-helper 1-type antitumor immune response, which is enhanced in cooperation with IFN-alpha.