Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts
Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts
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DOI：
10.1158/0008-5472.can-03-3911
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发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Nukiwa, T
中科院分区：
文献类型：
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作者：
Andarini, S;Kikuchi, T;Nukiwa, T
OX40配体(OX40L)是活化的CD4(+)T细胞上OX40的配体，具有建立有效的T细胞免疫的佐剂特性，T细胞免疫是免疫系统对抗癌症的有效效应臂。本研究的假设是，在体内通过基因工程表达OX40L的肿瘤细胞将通过OX40L-OX40的结合刺激肿瘤特异性T细胞，从而诱导全身抗肿瘤免疫。为了研究这一假说，S.C.用表达小鼠OX40L的重组腺病毒载体(AdOX40L)瘤内注射对3种不同的小鼠肿瘤细胞(B16黑色素瘤H-2(B)、Lewis肺癌H-2(B)和结肠-26结肠腺癌H-2(D))进行治疗。在所有测试的肿瘤模型中，AdOX40L治疗荷瘤小鼠显著抑制了肿瘤生长，并提高了治疗小鼠的生存能力。在体内，AdOX40L修饰的肿瘤诱导了治疗宿主中的肿瘤特异性细胞毒性T淋巴细胞，这与体内以肿瘤特异性方式启动T辅助1免疫反应有关。与这一发现一致的是，瘤内注射AdOX40L所提供的抗肿瘤作用在CD4(+)T细胞缺陷或CD8(+)T细胞缺陷的情况下完全被取消。此外，在免疫攻击实验中，转导AdOX40L的B16细胞也能诱导B16特异性的细胞毒T淋巴细胞反应，并能显著抑制B16肿瘤的生长。所有这些结果都支持这样一个概念，即用重组OX40L腺病毒载体对肿瘤细胞进行基因修饰可能有助于癌症免疫治疗方案的制定。
OX40 ligand (OX40L), the ligand for OX40 on activated CD4(+) T cells, has adjuvant properties for establishing effective T-cell immunity, a potent effector arm of the immune system against cancer. The hypothesis of this study is that in vivo genetic engineering of tumor cells to express OX40L will stimulate tumor-specific T cells by the OX40L-OX40 engagement, leading to an induction of systemic antitumor immunity. To investigate this hypothesis, s.c. established tumors of three different mouse cancer cells (B16 melanoma, H-2(b); Lewis lung carcinoma, H-2(b); and Colon-26 colon adenocarcinoma, H-2(d)) were treated with intratumoral injection of a recombinant adenovirus vector expressing mouse OX40L (AdOX40L). In all tumor models tested, treatment of tumor-bearing mice with AdOX40L induced a significant suppression of tumor growth along with survival advantages in the treated mice. The in vivo AdOX40L modification of tumors evoked tumor-specific cytotoxic T lymphocytes in the treated host correlated with in vivo priming of T helper 1 immune responses in a tumor-specific manner. Consistent with the finding, the antitumor effect provided by intratumoral injection of AdOX40L was completely abrogated in a CD4(+) T cell-deficient or CD8(+) T cell-deficient condition. In addition, ex vivo AdOX40L-transduced B16 cells also elicited B16-specific cytotoxic T lymphocyte responses, and significantly suppressed the B16 tumor growth in the immunization-challenge experiment. All of these results support the concept that genetic modification of tumor cells with a recombinant OX40L adenovirus vector may be of benefit in cancer immunotherapy protocols.