Silencing IDO2 in dendritic cells: A novel strategy to strengthen cancer immunotherapy in a murine lung cancer model

Abstract

While dendritic cell (DC)-based immunotherapy has achieved satisfactory results in animal models, its effects were not satisfactory as initially expected in clinical applications, despite the safety and varying degrees of effectiveness in various types of cancer. Improving the efficacy of the DC-based vaccine is essential for cancer immunotherapy. The present study aimed to investigate methods with which to amplify and enhance the antitumor immune response of a DC-based tumor vaccine by silencing the expression of indoleamine 2,3-dioxygenase 2 (IDO2), a tryptophan rate-limiting metabolic enzyme in DCs. In vitro experiments revealed that the silencing of IDO2 in DCs did not affect the differentiation of DCs, whereas it increased their expression of costimulatory molecules following stimulation with tumor necrosis factor (TNF)-α and tumor lysate from Lewis lung cancer (LLC) cells. In a mixed co-culture system, the IDO2-silenced DCs promoted the proliferation of T-cells and reduced the induction of regulatory T-cells (Tregs). Further in vivo experiments revealed that the silencing of IDO2 in DCs markedly suppressed the growth of tumor cells. Moreover, treatment with the IDO2-silenced DC-based cancer vaccine enhanced cytotoxic T lymphocyte activity, whereas it decreased T-cell apoptosis and the percentage of CD4 + CD25 + Foxp3 + Tregs. On the whole, the present study provides evidence that the silencing of the tryptophan rate-limiting metabolic enzyme, IDO2, has the potential to enhance the efficacy of DC-based cancer immunotherapy.

Prognostic Risk Signature and Comprehensive Analyses of Endoplasmic Reticulum Stress-Related Genes in Lung Adenocarcinoma

“…Targeting CD27 antibody synergizes with PD-L1 blockade to enhance the activation of CD4+ T cells and the proliferation and function of CD8+ T cells [ 57 ]. The silencing of IDO2 in DC not only negatively regulated the growth of tumor cells but also helped to improve the immunotherapeutic effect of DC-based cancers [ 58 ]. Interestingly, although there was no difference in PD-1 and CTLA-4 expression between the HR and LR groups, TIDE score was high in the HR group.…”

Tryptophan and Its Metabolites in Lung Cancer: Basic Functions and Clinical Significance

“…Similar to the function of IDO1, upregulated IDO2 expression is linked to worse prognosis in NSCLC (53). Therefore, IDO2 inhibitors may be valuable for targeting LC and IDO2 may be a biomarker for immunotherapy (69). Moreover, there is little information on whether IDO2 expression is associated with resistance to cisplatin in LC patients and what the value of IDO2 is in diagnosis and prognosis of LC (26,63).…”

Trial watch: Dendritic cell (DC)-based immunotherapy for cancer

“… 175 Liu et al (Jiangxi University of Technology, Nanchang, China), showed that silencing indoleamine 2,3-dioxygenase 2 (IDO2) in DCs improved their immunogenicity, leading to enhanced cytotoxic T cell activity and decreased Tregs within the tumors post-vaccination, as well as suppression of tumor growth. 176 Previously, Endo et al (Hokkaido University, Sapporo, Japan) had obtained similar results for increased antitumor effect of DC vaccines by silencing of indoleamine 2,3-dioxygenase 1 (IDO1) in DCs through administration of a siRNA via a nanodevice. 177 …”