Gene silencing of indoleamine 2,3-dioxygenase 1 inhibits lung cancer growth by suppressing T-cell exhaustion.

Content Provider	Europe PMC
Author	Shang, Ke Wang, Zhigang Hu, Yinying Huang, Yanqin Yuan, Keng Yu, Yanrong
Copyright Year	2020
Abstract	Indoleamine 2,3-dioxygenase 1 (IDO1), which degrades the essential amino acid tryptophan, exerts immunosuppressive functions and serves a crucial role in multiple types tumor progression, including non-small-cell lung cancer (NSCLC) and melanoma. Recent studies have reported that T-cell exhaustion is increased during tumor progression, which impairs the antitumor immune response. However, the association between IDO1 and T-cell exhaustion during tumor progression remains unknown. The present study evaluated the effect of IDO1 on T-cell exhaustion in lung cancer mice. The present study demonstrated that IDO1 knockdown by small interfering RNA in the LLC cell line inhibited T-cell exhaustion. Furthermore, the role of IDO1 in T-cell exhaustion during lung cancer progression was determined in an in vivo mouse model using IDO1 short hairpin RNA (shRNA). The results demonstrated that inhibition of IDO1 activity by shRNA administration in vivo significantly delayed the onset and growth of tumors. In addition, the expression levels of the inhibitory receptors programmed death-1 (PD-1) and B and T lymphocyte attenuator (BTLA) were increased in T-cells from the lung tumor-bearing mice, whereas interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) levels in serum were decreased compared with the control mice. However, no difference in the absolute number of T cells was observed, including CD4+ and CD8+ T cells. In addition, IDO1 knockdown by shRNA inhibited T-cell exhaustion in lung tumor-bearing mice, which was characterized by decreased expression of PD-1 and BTLA on T cells. By contrast, IL-2 and TNF-α levels in serum were increased in IDO1-shRNA-treated mice. By using a shRNA approach, the present study demonstrated that IDO1 activity may be involved in tumor growth, and that IDO1 silencing may inhibit tumor progression by impeding the process of T-cell exhaustion.
ISSN	17921074
Journal	Oncology Letters
Volume Number	19
PubMed Central reference number	PMC7202272
Issue Number	6
PubMed reference number	32382333
e-ISSN	17921082
DOI	10.3892/ol.2020.11477
Language	English
Publisher	D.A. Spandidos
Publisher Date	2020-03-27
Access Restriction	Open
Rights License	This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Copyright: © Shang et al.
Subject Keyword	lung cancer indoleamine 2,3 dioxygenase 1 T-cell exhaustion immunotherapy
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology