Potential biomarker and therapeutic target of indoleamine 2,3-dioxygenase (IDO) in bladder cancer

Abstract

Bladder cancer (BC) is among the most common urinary system. Although the most common form is the non-muscle invasive, many of these cases progress to muscle-invasive form, especially after transurethral resection which is the most used treatment. The vaccine with BCG has been used as adjuvant therapy, but a significant portion of patients still present recurrence of the disease. Indoleamine 2,3-dioxygenase (IDO) is an enzyme expressed in tissues where immunomodulation is necessary, including maternal-fetal interface, where the presence of IDO protects the semi-allogeneic embryo. Because IDO is expressed in some cancers, it is believed to promote tumor immune escape. In this context, studies of IDO inhibitors become promising, including some already in clinical phase. In BC, its role has not been elucidated, but we believe that IDO also participate in non-immunological events for tumor progression. There is strong evidence that BCG vaccine can induce IFN-gamma production, the most potent inducer of IDO. Moreover, the CD39 molecule may be induced by BCG and, through the production of adenosine and its derivatives, promote increase of IDO.The aim of this study is to evaluate the participation of IDO molecule in the BC in order to validate it as a biomarker of prognosis and target therapy. The expression of IDO and CD39 will be analyzed in human BC specimens acquired by transurethral resection or patients with no recurrence of the disease. We will correlate these protein expression with tumor grade, pathological stage, the response to BCG, tumor recurrence, recurrence rate and tumor progression. For cell culture, the study is to analyze the effect of BCG on expression of IDO and CD39, as well as the effect on cellular events (proliferation, cell death and invasive phenotype) and molecular (PI3K-mTOR and RTK-ras MAPK), in addition to the effect of IDO inhibitors and CD39 on these parameters. Through the animal model, we will evaluate the effect of BCG association with IDO inhibitors on tumor growth, local invasiveness and tumor immune response.With the expected results, we can demonstrate the possible relationship of IDO with the progression of BC and demonstrates the possible relationship of IDO with therapy with BCG, generating knowledge about the pathophysiological mechanisms of the disease, which can be explored from the point view diagnosis / prognosis and therapy. (AU)