Inactivated Sendai virus particles eradicate tumors by inducing immune responses through blocking regulatory T cells
Inactivated Sendai virus particles eradicate tumors by inducing immune responses through blocking regulatory T cells
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DOI：
10.1158/0008-5472.can-06-1615
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发表时间：
2007-01-01
期刊：
影响因子：
11.2
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
--
作者：
Kurooka, Masayuki;Kaneda, Yasufumi
紫外线灭活、复制缺陷的仙台病毒颗粒[日本包膜血凝病毒(HVJ-E)]注射到同基因BALB/c小鼠体内生长的小鼠结肠癌(CT26)肿瘤中，可根除60%至80%的肿瘤，并明显抑制剩余肿瘤的生长。诱导的适应性抗肿瘤免疫反应在肿瘤清除过程中占主导地位，因为这种作用在严重联合免疫缺陷小鼠中被取消。体外培养的小鼠和人树突状细胞在HVJ-E作用下呈剂量依赖性成熟。经HVJ-E刺激后树突状细胞分泌的细胞因子谱显示，其释放的白介素6(IL-6)量与活体HVJ所产生的量相当。实时定量逆转录-聚合酶链式反应和免疫组织化学检测显示，HVJ-E可诱导树突状细胞和CD_4~(+)、CD_8~(+)T细胞明显渗入肿瘤组织。此外，在CD8(+)T细胞以CD4(+)CD25(-)T细胞依赖的方式增强激活的证据下，CT26特异性CTL被诱导。另一方面，经HVJ-E刺激的树突状细胞的条件培养液可将CD4(+)CD25(-)效应T细胞从Foxp3(+)CD4(+)CD25(+)调节性T细胞(Treg)介导的抑制中解救出来，IL-6可能是这一现象的主导因素。我们还在活体内用HVJ-E治疗的小鼠中证实了这种拯救。此外，在体内阻断IL-6信号可显著降低HVJ-E的抗肿瘤作用。这是第一个表明单独使用HVJ-E可以根除肿瘤及其诱导抗肿瘤免疫反应的机制的报告。由于它可以增强抗肿瘤免疫，同时消除Treg介导的抑制，因此HVJ-E有望成为癌症免疫治疗的一种新疗法。
UV-inactivated, replication-defective Sendai virus particles [hemagglutinating virus of Japan envelope (HVJ-E)] injected into murine colon carcinoma (CT26) tumors growing in syngeneic BALB/c mice eradicated 60% to 80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive antitumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient mice. Murine and human dendritic cells underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by dendritic cells after HVJ-E stimulation showed that the amount of interleukin-6 (IL-6) released was comparable to that elicited by live HVJ. Real-time reverse transcription-PCR and immunohistochemistry revealed that HVJ-E induced a remarkable infiltration of dendritic cells and CD4(+) and CD8(+) T cells into tumors. In addition, CT26-specific CTLs were induced with the evidence of enhanced CD8(+) T-cell activation in a CD4(+)CD25(-) T cell-dependent manner. On the other hand, conditioned medium from dendritic cells stimulated by HVJ-E rescued CD4(+)CD25(-) effector T-cell proliferation from Foxp3(+)CD4(+)CD25(+) regulatory T cell (Treg)-mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, antitumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. This is the first report to show that HVJ-E alone can eradicate tumors and the mechanism through which it induces antitumor immune responses. Because it can enhance antitumor immunity and simultaneously remove Treg-mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.