Lu Yong, Zhang Mingjun, Wang Siqing, Hong Bangxing, Wang Zhiqiang, Li Haiyan, Zheng Yuhuan, Yang Jing, Davis Richard E, Qian Jianfei, Hou Jian, Yi Qing
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130061, China.
Nat Commun. 2014 Jun 24;5:4229. doi: 10.1038/ncomms5229.
Dendritic cell (DC)-based cancer immunotherapy is a promising method, but so far has demonstrated limited clinical benefits. Regulatory T cells (Tregs) represent a major obstacle to cancer immunotherapy approaches. Here we show that inhibiting p38 MAPK during DC differentiation enables DCs to activate tumour-specific effector T cells (Teff), inhibiting the conversion of Treg and compromising Treg inhibitory effects on Teff. Inhibition of p38 MAPK in DCs lowers expression of PPARγ, activating p50 and upregulating OX40L expression in DCs. OX40L/OX40 interactions between DCs and Teff and/or Treg are critical for priming effective and therapeutic antitumour responses. Similarly, p38 MAPK inhibition also augments the T-cell stimulatory capacity of human monocyte-derived DCs in the presence of Treg. These findings contribute to ongoing efforts to improve DC-based immunotherapy in human cancers.
基于树突状细胞(DC)的癌症免疫疗法是一种很有前景的方法,但迄今为止临床疗效有限。调节性T细胞(Tregs)是癌症免疫治疗方法的主要障碍。在这里,我们表明在DC分化过程中抑制p38丝裂原活化蛋白激酶(MAPK)可使DC激活肿瘤特异性效应T细胞(Teff),抑制Treg的转化并削弱Treg对Teff的抑制作用。DC中p38 MAPK的抑制降低了PPARγ的表达,激活了p50并上调了DC中OX40L的表达。DC与Teff和/或Treg之间的OX40L/OX40相互作用对于引发有效的治疗性抗肿瘤反应至关重要。同样,在存在Treg的情况下,p38 MAPK抑制也增强了人单核细胞衍生DC的T细胞刺激能力。这些发现有助于持续努力改善人类癌症中基于DC的免疫疗法。