Interleukin-4 gene transduced tumor cells promote a potent tumor-specific Th1-type response in cooperation with interferon-α transduction

被引:19
|
作者
Eguchi, J
Hiroishi, K
Ishii, S
Baba, T
Matsumura, T
Hiraide, A
Okada, H
Imawari, M
机构
[1] Showa Univ, Sch Med, Dept Internal Med 2, Shinagawa Ku, Tokyo 1428666, Japan
[2] Univ Pittsburgh, Inst Canc, Dept Neurosurg & Surg, Pittsburgh, PA USA
关键词
interleukin-4; interferon-alpha; cytotoxic T lymphocyte; helper Th1-type immune response; granulocytes; cytokine gene therapy;
D O I
10.1038/sj.gt.3302401
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:733 / 741
页数:9
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