Kannappan Vinodh, Butcher Kate, Trela Malgorzata, Nicholl Iain, Wang Weiguang, Attridge Kesley
Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK.
School of Life and Health Sciences, MB Building, Aston University, Aston Triangle, B4 7ET, Birmingham, UK.
Cancer Immunol Immunother. 2017 May;66(5):637-645. doi: 10.1007/s00262-017-1970-6. Epub 2017 Feb 27.
IL-21 is known to promote anti-tumour immunity due to its ability to promote T cell responses and counteract Treg-mediated suppression. It has also been shown to limit Treg frequencies during tumour-antigen stimulations. However, whether this represents inhibition of FOXP3 induction in naïve CD4 T cells or curtailed expansion of natural Treg remains unclear. Moreover, whether this effect is maintained in an environment of tumour-derived immunosuppressive factors is not known. Here, we show that in the context of a number of cancers, naïve CD45RA+ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumours secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. We conclude that Treg induction in naïve T cells is a common phenomenon amongst a number of different cancers and that the ability of IL-21 to counteract this effect is further evidence of its promise in cancer therapy.
已知白细胞介素-21（IL-21）可促进抗肿瘤免疫，因为它能够促进T细胞反应并抵消调节性T细胞（Treg）介导的抑制作用。研究还表明，它在肿瘤抗原刺激过程中可限制Treg频率。然而，这是代表对初始CD4 T细胞中叉头框蛋白3（FOXP3）诱导的抑制，还是天然Treg的扩增受到抑制，仍不清楚。此外，在肿瘤衍生的免疫抑制因子环境中这种效应是否得以维持尚不清楚。在此，我们表明，在多种癌症背景下，初始CD45RA+ CD4 T细胞被诱导表达高水平的FOXP3，且FOXP3表达与T细胞增殖抑制相关。分泌高水平总活性转化生长因子β1（TGFβ1）的肿瘤最有效地诱导了FOXP3表达，而IL-21可有效抵消这种诱导作用，恢复T细胞增殖。我们得出结论，初始T细胞中Treg的诱导在多种不同癌症中是一种常见现象，并且IL-21抵消这种效应的能力进一步证明了其在癌症治疗中的前景。
