Division of Gene and Immune Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
J Immunol. 2013 Sep 15;191(6):3440-52. doi: 10.4049/jimmunol.1201454. Epub 2013 Aug 21.
Lymphopenia-induced homeostatic proliferation of T cells after autologous hematopoietic stem cell transplantation (HSCT) skews the T cell repertoire by engaging tumor-associated Ags, leading to an induction of antitumor immunity. However, how HSCT alters the immunosuppressive microenvironment in the tumors is unknown. In this study, we first analyzed the kinetics of regulatory T cells (Tregs) in the tumors after syngeneic HSCT. Unexpectedly, the frequency of CD4⁺ cells expressing Foxp3 was increased in the spleens, whereas the frequency was clearly decreased in the tumors after HSCT. The origin of reconstituted CD4⁺ and Foxp3⁺ cells in the tumors was mainly from the expansion of transferred splenic T cells. Then, to examine the mechanism of Treg suppression after HSCT, we isolated CD11c⁺ cells from tumors. A large amount of Treg-inhibitory cytokine IL-6 was secreted from the CD11c⁺ cells in the tumors, but not in the spleens in the recipient mice. Furthermore, to understand what factor affects the activity of CD11c⁺ cells in the tumors after HSCT, we analyzed the expression of various cytokines/chemokines with mouse cytokine Ab arrays, and noticed that VEGF-D concentration was increased in the tumors in the early period after HSCT. The CD11c⁺ cells produced IL-6 in response to VEGF-D stimulation, and an administration of VEGF receptor-3 neutralizing Ab significantly suppressed the production of IL-6 from CD11c⁺ cells accompanied with the increase of Tregs in the tumors of HSCT recipients. Autologous HSCT creates an environment that strongly supports the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the suppression of Tregs.
自体造血干细胞移植 (HSCT) 后，淋巴细胞减少诱导的 T 细胞同源性增殖通过与肿瘤相关抗原结合，使 T 细胞库发生偏倚，从而诱导抗肿瘤免疫。然而，HSCT 如何改变肿瘤中的免疫抑制微环境尚不清楚。在这项研究中，我们首先分析了同基因 HSCT 后肿瘤中调节性 T 细胞 (Treg) 的动力学。出乎意料的是，Foxp3 表达的 CD4⁺细胞在脾脏中的频率增加，而 HSCT 后在肿瘤中的频率明显降低。肿瘤中再构成的 CD4⁺和 Foxp3⁺细胞的起源主要来自转移的脾脏 T 细胞的扩增。然后，为了研究 HSCT 后 Treg 抑制的机制，我们从肿瘤中分离出 CD11c⁺细胞。大量的 Treg 抑制细胞因子 IL-6 从肿瘤中的 CD11c⁺细胞中分泌，但不在受体小鼠的脾脏中分泌。此外，为了了解什么因素影响 HSCT 后肿瘤中 CD11c⁺细胞的活性，我们用小鼠细胞因子 Ab 阵列分析了各种细胞因子/趋化因子的表达，并且注意到 VEGF-D 浓度在 HSCT 后早期增加。CD11c⁺细胞在 VEGF-D 刺激下产生 IL-6，并且 VEGF 受体-3 中和 Ab 的给药显著抑制了 CD11c⁺细胞产生 IL-6，同时 HSCT 受体肿瘤中的 Treg 增加。自体 HSCT 通过抑制 Treg ，为重建的淋巴细胞减少受者创造了一个强烈支持增强抗肿瘤免疫的环境。
