GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.
GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability.
复制标题
DOI：
10.1158/2326-6066.cir-13-0086
复制
发表时间：
2013-11
影响因子：
10.1
通讯作者：
Wolchok JD
中科院分区：
文献类型：
--
作者：
Schaer DA;Budhu S;Liu C;Bryson C;Malandro N;Cohen A;Zhong H;Yang X;Houghton AN;Merghoub T;Wolchok JD
最近，激动型抗体连接GITR(糖皮质激素诱导的肿瘤坏死因子受体相关基因，或TNFRSF18)已进入治疗晚期恶性肿瘤的早期临床试验。尽管GITR调节诱导肿瘤消退的能力在临床前研究中得到了很好的证实，但其潜在的作用机制，特别是其对CD4+Foxp3+调节性T细胞(Treg)的影响，尚未完全阐明。我们先前已经证明，激动型抗体DTA-1在体内连接GITR可导致肿瘤内Treg减少50%，并下调Foxp3的表达。我们在这里表明，Foxp3的缺失是肿瘤依赖性的。用DTA-1处理后，过继转移的Foxp3+Treg在宿主体内失去了Foxp3的表达，而来自幼稚小鼠的Treg保持了Foxp3的表达。GITR连接也改变了对Treg功能至关重要的各种转录因子和细胞因子的表达。肿瘤内Treg中完整的Foxp3缺失与Helios表达的急剧下降相关，并与转录因子T-Bet和eome的上调有关。在DTA-1治疗的Treg中，Helios的变化与IL-10的减少和干扰素γ的表达增加相一致。综上所述，这些数据表明，GITR激动剂抗体改变Treg谱系稳定性，诱导炎症效应T细胞表型。由此导致的谱系稳定性的丧失导致Treg失去了肿瘤内的免疫抑制功能，使肿瘤容易受到肿瘤特异性效应CD8+T细胞的杀伤。
Ligation of GITR (glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene, or TNFRSF18) by agonist antibody has recently entered into early phase clinical trials for the treatment of advanced malignancies. Although the ability of GITR modulation to induce tumor regression is well-documented in preclinical studies, the underlying mechanisms of action, particularly its effects on CD4+foxp3+ regulatory T cells (Treg), have not been fully elucidated. We have previously demonstrated that GITR ligation in vivo by agonist antibody DTA-1 causes a >50% reduction of intra-tumor Treg with down modulation of Foxp3 expression. Here we show that the loss of Foxp3 is tumor-dependent. Adoptively-transferred Foxp3+Treg from tumor-bearing animals lose Foxp3 expression in the host when treated with DTA-1, whereas Treg from naïve mice maintain Foxp3 expression. GITR ligation also alters the expression of various transcription factors and cytokines important for Treg function. Complete Foxp3 loss in intra-tumor Treg correlates with a dramatic decrease in Helios expression and is associated with the upregulation of transcription factors T-Bet and Eomes. Changes in Helios correspond with a reduction in IL-10 and an increase in IFNγ expression in DTA-1-treated Treg. Together, these data show that GITR agonist antibody alters Treg lineage stability inducing an inflammatory effector T cell phenotype. The resultant loss of lineage stability causes Treg to lose their intra-tumor immune suppressive function, making the tumor susceptible to killing by tumor-specific effector CD8+ T cells.