Ablation of Cbl-b provides protection against transplanted and spontaneous tumors
Ablation of Cbl-b provides protection against transplanted and spontaneous tumors
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DOI：
10.1172/jci29472
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Gu, Hua
中科院分区：
文献类型：
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作者：
Chiang, Jeffrey Y.;Jang, Ihn Kyung;Gu, Hua
旨在诱导有效抗肿瘤免疫反应的努力面临的一个重大挑战是，在这些反应中发挥重要作用的CD8+T细胞可能无法对缺乏共刺激信号且受到免疫抑制环境（例如由肿瘤细胞本身产生的TGF-β或浸润性Treg介导的免疫抑制环境）保护的肿瘤作出反应，常常导致肿瘤特异性T细胞的耐受或无反应。在这里，我们证明Cb1b(-/-) CD8(+) T细胞的体外激活不依赖于CD28共刺激并且对TGF-β抑制具有抵抗力。体内研究进一步表明，Cb1b(-/-) 小鼠（而非 WT 对照）能够有效排斥不表达 137 个配体的接种的 E.G7 和 EL4 淋巴瘤，并且将 Cb1b(-/-) 突变引入易患肿瘤的共济失调毛细血管扩张突变缺陷小鼠中显着降低了自发性胸腺淋巴瘤的发病率。免疫组织学研究表明，Cblb(-/-)小鼠的E.G7肿瘤含有大量浸润的CD8(+) T细胞。将纯化的 Cblb(-/-) CD8(+) T 细胞过继转移至 E.G7 荷瘤小鼠体内，可有效根除已形成的肿瘤。因此，我们的数据表明，Cb1-b 的消融可能是引发针对接种肿瘤和自发肿瘤的免疫反应的有效策略。
A significant challenge to efforts aimed at inducing effective antitumor immune responses is that CD8(+) T cells, which play a prominent role in these responses, may be unable to respond to tumors that lack costimulatory signals and that are protected by an immune suppressive environment such as that mediated by TGF-beta produced by tumor cells themselves or by infiltrating Tregs, often resulting in tolerance or anergy of tumor-specific T cells. Here we show that the in vitro activation of Cb1b(-/-) CD8(+) T cells does not depend on CD28 costimulation and is resistant to TGF-beta suppression. In vivo studies further demonstrated that Cb1b(-/-) mice, but not WT controls, efficiently rejected inoculated E.G7 and EL4 lymphomas that did not express 137 ligands and that introduction of the Cb1b(-/-) mutation into tumor-prone ataxia telangiectasia mutated-deficient mice markedly reduced the incidence of spontaneous thymic lymphomas. Immunohistological study showed that E.G7 tumors from Cblb(-/-) mice contained massively infiltrating CD8(+) T cells. Adoptive transfer of purified Cblb(-/-) CD8(+) T cells into E.G7 tumor-bearing mice led to efficient eradication of established tumors. Thus, our data indicate that ablation of Cb1-b can be an efficient strategy for eliciting immune responses against both inoculated and spontaneous tumors.