Interleukin 12 stimulates IFN-gamma-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance.
Interleukin 12 stimulates IFN-gamma-mediated inhibition of tumor-induced regulatory T-cell proliferation and enhances tumor clearance.
复制标题
DOI：
10.1158/0008-5472.can-09-1145
复制
发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Ley TJ
中科院分区：
文献类型：
--
作者：
Cao X;Leonard K;Collins LI;Cai SF;Mayer JC;Payton JE;Walter MJ;Piwnica-Worms D;Schreiber RD;Ley TJ
为了确定在肿瘤环境中调节调节性T（Treg）细胞的因子，我们将各种肿瘤细胞与纯化的Treg细胞或与未分级的脾细胞共培养。我们发现Treg扩增仅发生在未分级的脾细胞中，这表明辅助细胞和/或由它们产生的因子在肿瘤诱导的Treg扩增中起重要作用。我们对肿瘤相关Treg细胞进行基因表达谱分析，以鉴定候选信号分子，并研究其对肿瘤诱导的Treg扩增的影响。我们无意中发现IL-12治疗以IL-12受体依赖性方式阻断Treg扩增。另外的研究表明，IL-12通过刺激干扰素-γ介导的Treg细胞增殖抑制而起作用，这可以部分解释IL-12的抗肿瘤作用。此外，发现IL-12处理降低IL-2产生，这可能导致Treg细胞的干扰素-γ非依赖性抑制，因为IL-2是其存活和扩增所需的。机制研究揭示，干扰素-γ信号传导直接导致Treg细胞中的细胞周期停滞。该研究表明IL-12-干扰素-γ轴可以抑制肿瘤诱导的Treg增殖。这种机制可能会抵消Treg细胞在体内促进肿瘤生长的能力。
To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we co-cultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that IL-12 treatment blocked Treg expansion in an IL-12 receptor-dependent fashion. Additional studies showed that IL-12 acts by stimulating Interferon-gamma mediated inhibition of Treg cell proliferation, which may partially account for the anti-tumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to interferon-gamma independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that Interferon-gamma signaling directly causes cell cycle arrest in Treg cells. This study demonstrates that an IL-12-Interferon-gamma axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo.