Current Challenges for IDO2 as Target in Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors have revolutionized the clinical approach of untreatable tumors and brought a breath of fresh air in cancer immunotherapy. However, the therapeutic effects of these drugs only cover a minority of patients and alternative immunotherapeutic targets are required. Metabolism of l-tryptophan (Trp) via the kynurenine pathway represents an important immune checkpoint mechanism that controls adaptive immunity and dampens exaggerated inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme catalyzing the first, rate–limiting step of the pathway, is expressed in several human tumors and IDO1 catalytic inhibitors have reached phase III clinical trials, unfortunately with disappointing results. Although much less studied, the IDO1 paralog IDO2 may represent a valid alternative as drug target in cancer immunotherapy. Accumulating evidence indicates that IDO2 is much less effective than IDO1 in metabolizing Trp and its functions are rather the consequence of interaction with other, still undefined proteins that may vary in distinct inflammatory and neoplastic contexts. As a matter of fact, the expression of IDO2 gene variants is protective in PDAC but increases the risk of developing tumor in NSCLC patients. Therefore, the definition of the IDO2 interactome and function in distinct neoplasia may open innovative avenues of therapeutic interventions.

Targeting Tryptophan Catabolism in Cancer Immunotherapy Era: Challenges and Perspectives

“…Three enzymes catalyze the rate-limiting step of the KP that transforms Trp into a series of biologically active metabolites: IDO1, IDO2 and TDO2 (Figure 1). Contrary to the uncertain role and regulation of IDO2, IDO1 and TDO2 are well-characterized intracellular heme-containing metalloproteins that are responsible for the degradation of the majority of Trp intake (19).…”

Indoleamine 2,3-dioxygenase 2 Immunohistochemical Expression in Medullary Thyroid Carcinoma: Implications in Prognosis and Immunomodulatory Effects

“…IHC results indicated that the IDO2 expression of lymph node tissues was signi cantly related to the metastasis status (P=0.002; Table 5). Previous studies have not reported such a remarkable effect of IDO2 on lymph node metastatic status (55), suggesting that IDO2 may play distinct roles based on the pathophysiologic feature or immune microenvironment of different cancers. Moreover, survival analysis suggests that high expression of IDO2 tends to result in a worse prognosis in patients with MTC.…”

The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment

“…Although IDO2 can also initiate the Trp pathway, the affinity and catalytic efficacy of IDO2 for the substrate are very low [ 2 ]. Therefore, IDO2 may have little effect on the whole Trp metabolism [ 3 , 4 , 5 ]. The expression level of IDO1 closely correlates with poor prognosis of tumor, and IDO1 inhibitors have shown significantly limit tumor growth [ 6 , 7 , 8 , 9 , 10 ].…”