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首页> 外文期刊>Journal of Translational Medicine >Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor
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Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor

机译：肿瘤特异性T细胞通过淋巴毒素β受体发出肿瘤破坏信号

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Background Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells. Methods Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays. Results Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p Conclusion The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.
机译：背景以前，我们报道过继转移的perforin k / o（PKO）和IFN-γk / o（GKO）或perforin /IFN-γdouble k / o（PKO / GKO）效应T细胞介导了B16BL6-的降解。 D5（D5）肺转移，显示TNF受体信号传导在介导肿瘤消退中起关键作用。在本报告中，我们研究了淋巴毒素-（LT-α）作为肿瘤特异性效应T细胞的潜在效应分子的作用。方法从野生型，GKO型，LT-α缺陷型（LKO）或PKO / GKO小鼠的肿瘤疫苗引流淋巴结（TVDLN）中产生效应T细胞，并检测它们在存在或不存在时介导D5肺转移消退的能力。缺少LT-βR-Fc融合蛋白或抗IFN-γ抗体。通过ELISA，RT-PCR和趋化性测定法确定D5肿瘤细胞产生的趋化因子。结果wt，GKO或PKO / GKO小鼠刺激的效应T细胞表达了LT-β受体（LT-βR）的配体。发现D5肿瘤细胞组成性表达LT-βR。 LT-βR-Fc融合蛋白的使用完全废除了GKO或PKO / GKO的治疗功效，但不能废除wt效应T细胞（p结论效应T细胞在体内的LT-α表达对体内抗肿瘤活性的贡献尚不清楚）当研究wt效应T细胞时，LT-βR信号转导对GKO或PKO / GKO效应T细胞的贡献被确定，因为LT-α不会直接诱导D5肿瘤细胞的体外杀伤，但会刺激D5肿瘤细胞分泌趋化因子，这些数据表明肿瘤特异性效应T细胞通过LT-βR在肿瘤细胞上的交联相互作用来表达LT-α，从而诱导趋化因子的分泌，而趋化因子是巨噬细胞的趋化因子。巨噬细胞在我们的系统中消除肿瘤需要进一步研究，该模型为与肿瘤消退同时发生的先天效应细胞浸润提供了可能的解释。

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