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

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.

IDO1 Modulates the Sensitivity of Epithelial Ovarian Cancer Cells to Cisplatin through ROS/p53-Dependent Apoptosis

“…IDO1 induces tumor-related immunosuppression by Trp depletion and Kyn accumulation, which result in dysfunction of natural killer (NK) cells/effector T cells and activate Tregs [ 4 ]. Previous data have manifested that IDO1 was highly expressed in multiple cancer tissues including ovarian cancer, and that a high expression level was associated with poor prognosis [ 5 , 6 , 7 , 8 , 9 ]. Okamoto et al found that 50% of ovarian cancer patients were IDO1-positive and that the overall survival was 11 months in patients with diffuse distribution compared with 41 months survival in patients with sporadic distribution [ 10 ].…”

Complex effect of continuous curcumin exposure on human bone marrow‐derived mesenchymal stem cell regenerative properties through matrix metalloproteinase regulation

“…47 Reduced IDO1 expression also inhibits T-cell exhaustion. 48 The up-regulation of IDO1 expression in hBM-MSCs could indicate that curcumin can enhance the immunomodulatory function of hBM-MSCs. The immunomodulatory action of curcumin-treated MSCs in autoimmune disease models and in heterologous transplantation should be examined in future investigations.…”

“…IDO1 can promote immune toleration through tryptophan catabolism and accumulation of tryptophan metabolites 47 . Reduced IDO1 expression also inhibits T‐cell exhaustion 48 . The up‐regulation of IDO1 expression in hBM‐MSCs could indicate that curcumin can enhance the immunomodulatory function of hBM‐MSCs.…”

From Melanoma Development to RNA-Modified Dendritic Cell Vaccines: Highlighting the Lessons From the Past

“…In the tumoral context, the cardinal functions of IDO are tryptophan depletion and kynurenine upregulation, which tilt the balance to immunosuppression ( 98 ). Recently, Shang et al have demonstrated that the tumoral IDO knockdown can substantially decrease the PD-1 expression on T-cells and increase the IL-2 plasmatic level in lung cancer-bearing mice ( 99 ). In line with that, it has been estimated that 37% of melanoma specimens express IDO, which its expression is substantially associated with tumoral PD-L1 expression and nodal metastasis ( 100 ).…”

“…Since IDO can also be expressed from tumoral cells ( 99 , 100 ), the silencing of DC-derived IDO might not suffice to downregulate the produced IDO in the tumor microenvironment. Epacadostat is an oral inhibitor of the IDO1 enzyme.…”