Indoleamine 2,3-Dioxygenase-1 Expression is Changed During Bladder Cancer Cell Invasion

Abstract

The severity of the bladder carcinoma (BC) is directly linked to cell invasion and metastasis. Indoleamine 2,3-dioxygenase-1 (IDO-1) is an INF-γ-induced immunomodulating enzyme that has been linked to the cancer cell invasiveness. Because IDO1 is variable among the tumors, we analyzed its expression in the BC invasion using BC mice models and cell culture. MB49 cells were orthotopically or ectopically inoculated in C57Bl6 mice to evaluate IDO1 by immunohistochemistry. For in vitro experiments, expression of IDO1 and INF-γ was evaluated in grade-1 (RT4) and in grade-3 (T24) BC cell lines. Invading and non-invading T24 cells were separated using the Matrigel/Transwell system, of which total RNA was extracted immediately or after 2 weeks of subculture. Finally, IDO1 was silenced in T24 cells to verify its role on cell invasiveness. In both animal models, IDO1 was differentially expressed between non-invading and invading cells. In cell culture, T24 cells expressed more IDO1 than RT4 cells, independently of the INF-γ expression. IDO1 was differentially expressed between non-invading and invading T24 cells, a difference that was lost by long-time subculture. IDO1 silencing resulted in diminished cell invasiveness. In conclusion, IDO1 expression is changed during bladder carcinoma invasion, playing an important role in this process.

Immune-checkpoint gene expression and BCG response in non-muscle invasive bladder cancer

“…Furthermore, IDO1 presented high expression levels in our cohort and despite it has not been associated with BCG-responsiveness, elevated levels of IDO1 were associated with poor overall survival. IDO1 is an INF-γ-induced immunomodulating enzyme that has been linked to the cancer cell invasiveness and its expression seems to be changed during bladder carcinoma invasion in pre-clinical models [ 51 ]. Addiotionally, IDO1 seems to promote epithelial-mesenchymal transition through PD-L1 pathway [ 52 ].…”

Breaking Barriers: Modulation of Tumor Microenvironment to Enhance Bacillus Calmette–Guérin Immunotherapy of Bladder Cancer

“…Kynurenine, an IDO product, activates the aryl hydrocarbon receptor (AhR), facilitating the differentiation of T cells into Tregs and contributing to immune tolerance [115]. The genetic makeup of individuals regulates IDO1 expression through the polymorphisms or mutations that regulate the IDO1 gene directly or modulate the regulatory pathways governing IDO1 expression [116][117][118]. Polymorphisms associated with heightened IDO1 activity, fostering a suppressive TME that is conductive of immune evasion [116][117][118], indicating their consideration in the therapeutic potential of IDO1-targeted interventions [119,120].…”

“…The genetic makeup of individuals regulates IDO1 expression through the polymorphisms or mutations that regulate the IDO1 gene directly or modulate the regulatory pathways governing IDO1 expression [116][117][118]. Polymorphisms associated with heightened IDO1 activity, fostering a suppressive TME that is conductive of immune evasion [116][117][118], indicating their consideration in the therapeutic potential of IDO1-targeted interventions [119,120]. Furthermore, chemotherapeutic agents can elevate IDO1 expression as a result of the cancer cell stress response [121,122].…”

Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer

“…Indoleamine 2,3-dioxygenase-1 (IDO1) has been recognised as a one of the markers of invasiveness. Indeed, IDO1 expression is reduced significantly in invasive compared with non-invasive BC cells [ 54 , 55 ].…”