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The transcription factor TOX is involved in the regulation of T-cell exhaustion in neuroblastoma

•NB-T cells are more subjected to exhaustion conversion upon restimulation.•TOX is involved in the regulation of NB-T cells exhaustion at multiple levels.•DNA methylation program of the TOX gene may be involved in the remodeling of NB-T cells exhaustion by regulating TOX expression. T-cell exhaustio...

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Published in:Immunology letters 2022-08, Vol.248, p.16-25
Main Authors: Pei, Mengmiao, Chai, Wenjia, Wang, Xiaolin, Duan, Yanlong, Wang, Hui, Xi, Yue, Mou, Wenjun, Wang, Wei, Chen, Xi, Zhang, Hui, Li, Qiliang, Song, Wenqi, Wang, Huanmin, Ma, Xiaoli, Gui, Jingang
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Language:English
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Summary:•NB-T cells are more subjected to exhaustion conversion upon restimulation.•TOX is involved in the regulation of NB-T cells exhaustion at multiple levels.•DNA methylation program of the TOX gene may be involved in the remodeling of NB-T cells exhaustion by regulating TOX expression. T-cell exhaustion is one of the key reasons for attenuated T-cell cytotoxicity against tumours. At both the expression and epigenetic levels, a number of genes, including the transcription factor TOX, are believed to be implicated in regulating T-cell exhaustion. In the present study, we found that in NB patients, the ratio of exhausted T cells, featuring upregulated PD-1 and Tim-3, was increased. Meanwhile, the expression of inhibitory surface receptors, including Lag-3, CD160, VISTA and KLRG1, was also increased, but this was accompanied by a reduced ability to release the effector molecules IL-2, IFN-γ, TNF-α and Granzyme B in CD3+ T cells from NB patients. It is noteworthy that NB-derived memory T cells (Tm) showed more obvious exhausted characteristics than other T cells. Moreover, the T cells from NB patients possessed a higher potential for exhaustion conversion upon in vitro TCR stimulation in our time-course culture experiment. In NB patients, T-cell exhaustion was demonstrated to correlate with the elevated expression of TOX in freshly sorted CD3+ T cells as well as in anti-CD3 stimulated PBMCs. Most importantly, our data supported the idea that the hypomethylation of the TOX promoter may be one of the initiators that regulates TOX expression and enables TOX to play a crucial role in T-cell exhaustion reprogramming in NB patients.
ISSN:0165-2478
1879-0542
DOI:10.1016/j.imlet.2022.06.004