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.
Highlights
Over the course of evolution, the metabolism of L-tryptophan (Trp), an essential amino acid for mammals, has evolved to be a primary control node in the regulation of immune responses [1]
To evaluate the contribution of genetic variation in IDO2 to the risk of non-small-cell lung cancer (NSCLC), we examined the frequencies of the two common single nucleotide polymorphisms (SNPs) in IDO2 as described above, namely rs10109853 (R248W) and rs4503083 (Y359X)
By resorting to a cohort involving 145 NSCLC patients and 395 healthy matched controls, we found that the R248W displays a significantly different genotype distribution between NSCLC patients and controls, with the genotypes that include the minor allele conferring almost a 2-fold increased risk of NSCLC (Table 1)
Summary
Over the course of evolution, the metabolism of L-tryptophan (Trp), an essential amino acid for mammals, has evolved to be a primary control node in the regulation of immune responses [1]. No evidence emerged from these studies revealing the molecular mechanism of IDO2 in regulating the autoimmune response in the arthritis model In line with these observations, in humans, the expression of an IDO2 variant lacking catalytic activity is associated with reduced risk of Crohn’s disease [7]. A perspective that could reconcile the apparent divergence of the results obtained in different experimental models of inflammation/autoimmunity is that the activity of IDO2 may be strictly related to the physiopathologic context and cellular microenvironment In support of this hypothesis, a recent study revealed that, in two different cohorts of patients with aspergillosis, specific and different patterns of IDO2 single nucleotide polymorphisms (SNPs) can be observed. The role of splicing events in IDO2 function remains unclear, the fact that the risk allele of R248W is TABLE 1 | Association test results of IDO2 genotypes and the risk of non-small-cell lung cancer (NSCLC). Reported to influence the intron-excision ratio of IDO2 suggests an effect on transcript diversity that may help explain its stronger association with NSCLC
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