IDO1, the best-studied enzyme of all KP, seems to play one of the most complex roles in cancerogenesis. TRP depletion in local milieu IDO1 affects immunological cells and silences immune response. The activation of GCN-2 kinase (general control nonderepressible 2 kinase) and the inhibition of mTOR (mechanistic target of rapamycin) pathway lead to an immunosuppressive phenotype and facilitated immunosurveillance escape by cancer cells. It has been discovered that IDO1 has a direct impact on malignant cells and enhances tumorigenesis by increasing angiogenesis and metastasis. Moreover, this enzyme conditions metabolite production which contributes to oncogenesis either through AhR (aryl hydrocarbon receptor) activation or in other mechanisms described below. Due to that fact, IDO1, as a pharmacological target, has a high potential in oncology and its inhibition gives an opportunity for increased therapeutic successes. The depletion of TRP affects dendritic cells and two populations of lymphocyte T—immunosuppressive regulatory Tcells (Treg) and cytotoxic lymphocyte T (Tc). TRP deficiency, through the activation of GNC-2, is a signal enhancing the expression of inhibitory receptors (ILT3, ILT4) in DCs
[19]. Those cells, as antigen-presenting cells (APCs) to lymphocytes T, as well take part in the differentiation of naïve Tcells in chosen subpopulations. The overexpression of ILTs, especially ILT3 and ILT4 on DCs, induces the differentiation of CD8+ and CD4+ Tcells into Treg
[20]. Additionally, in CD4+ Th cells, the presence of ILTs enhances their anergy, thus inhibits the antitumor role. A high expression of ILTs essential for Treg induction
[21] altogether favors the immunosuppressive phenotype. In general, those receptors are suspected to be a key factor inducing tolerogenicity
[22] thus developing immunological tolerance in host organisms. The role of immunoglobulin-like transcript receptors in cancer development has been reported previously
[23]. In few cancer types, such as breast, colorectal, non-small cell lung cancer, and renal cell carcinoma, high expression of those proteins was generally connected with more advanced stages of the disease, more often occurring metastasis, and poor prognosis for patients. The mentioned research points on the activation of ERK1/2 (extracellular signal-regulated kinases) signaling pathway, enhanced epithelial-to-mesenchymal transition (EMT), and increase in VEGF (vascular endothelial growth factor) level, which altogether contributes to augmented motility, angiogenesis, and invasiveness of cancer cells
[24][25][26][27]. The gathered information shows that TRP depletion affects immune cells, which has a direct impact on cancer cells, their increased motility, metastasis potential and results in patients’ worse prognosis and overall survival. Another structure affected by GCN-2 activation exerted by IDO-1-induced TRP depletion is ζ-chain of T-cell receptor (TCR) in CD8+ Tcells. This structure is a key agent which conditions the occurrence of signaling from TCR
[28], with the following activation of CD8+ and their full antitumor immune response
[29]. Therefore, its downregulation in case of non-sufficient TRP level interrupts the cascade of events with the following impairment in lymphocyte proliferation and cytokine production
[30]. To fully understand how the downregulation of the zeta chain in TCR affects tumor development, it is necessary to describe the role of CD8+ lymphocytes in this process. Those cells are at the highest level responsible for the direct killing of tumor cells through the secretion of cell membrane perforating molecules, i.e., cathepsin C, perforin, granzymes. The second mechanism, induced by CD8+ Tcells, which leads to cell apoptosis, is their expression of the Fas ligand, which, after binding to its receptor on the targeted cell, induces caspases and endonucleases leading to DNA impairment
[31]. Previously, it was shown that a low number of CD8+ Tcells correlates with enhanced tumor growth and poor prognosis
[32][33]. Detailed research points to a zeta chain as a key factor mediating antitumor response. In the case of oral cancer and Hodgkin’s Disease, a low level of the zeta chain in TCR in peripheral Tcells is correlated with a more advanced stage of disease
[34][35]. Moreover, enhancing TCR signaling by binding immunoglobulin superfamily member 4 (IGSF4) to the zeta chain significantly decreased tumor size and weight in murine models with implanted melanoma cells and reduces the occurrence of metastatic colonies.
[36]. Still, the high activity of IDO1, and thus a decreased TRP level leads to abnormal activity of immunosuppressive Tregs, whose pro-tumorigenic activity is based on crosstalk with other immune cells, as well as on a direct impact on cancer cells. Those cells express CD73 and CD39 endonucleotidases, which take part in adenosine production
[37]. The overexpression of the latter was connected to an increased number of occurring liver metastasis in colorectal cancer (CRC) in the murine model and correlates with the worst prognosis and a poor outcome in patients
[38]. Adenosine, whose production from ATP and AMP is enhanced in the presence of Treg, affects tumor development by activating PI3K/Akt/mTOR pathway and upregulating metalloproteinases that stimulate invasiveness and migration capacity of malignant cells
[39]. Additionally, the whole loop leading to adenosine excretion leads to angiogenesis, caused by an intensified production of VEGF
[40]. Besides the direct act on processes promoting oncogenesis, an elevated number of Tregs, and thus IDO1 activity, leads to the development of the immunosuppressive tumor microenvironment. High activity of Tregs limits interleukin 2 (IL-2) production, with the following CD8+ lymphocyte inhibition
[41]. Other cells from the immune system, whose activity is at least in part controlled by Tregs are cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, regulatory B cells (Bregs), and myeloid-derived suppressor cells
[42]. It should be emphasized here that the latter can secrete IDO1
[43], which loops the course of events even more. All of them are considered to be tumor promoters, their activity being increased under the impact of Treg. The outcomes of the experiments confirm the crucial role of Treg in cancerogenesis. In a few cancer types, i.e., gastric, breast, renal a higher intratumoral Treg level correlates with a worse prognosis
[44][45][46]. Additionally, it was reported that high Treg activity contributes to chemoresistance
[47][48]. On the other hand, clinical reports indicate the inhibition of inflammatory response by Treg, which in a further perspective leads to a decreased level of occurring tumor
[49]. Taking into account the double role of Treg in cancer development, and IDO1 effect on both subpopulations of lymphocytes—the downregulation of CD8+ cytotoxic Tcells and the upregulation of immunosuppressive Treg it seems reasonable to focus on the ratio between these lines as the most proper prognostic factor in the context of IDO1 activity
[50]. The outcomes from oncological patient samples confirm that a high CD8+/Treg ratio, and hence a low IDO1 activity, is associated with a more favorable prognosis
[51][52][53]. The described effects are the results obtained by the activation of GCN-2 kinase. However, it was mentioned before that TRP depletion affects mTOR kinase, with its inhibition. This results in a decreased number of cytotoxic and helper T cells and an increased number of immunosuppressive Treg in the general population. Besides an indirect impact of IDO1 on cancer cells, it excretes its own direct effect. In bladder cancer cells, IDO1 inhibition leads to a limited colony formation, an increased E-cadherin expression with a concomitantly reduced N-cadherin and vimentin presence. This in total points to IDO1 being a promoter of epithelial-to-mesenchymal transition and a factor that facilitates a gain in motility capacity by cancer cells. Moreover, in the same experiment, the authors show a reduced ability for tubule formation by HVUECs and thus decreased angiogenesis after silencing IDO1
[54]. Those results are in the line with the results obtained by Pan et al., who reported decreased cell invasiveness and migratory ability in lung cancer cells after IDO1 silencing
[55]. The same authors discovered that IDO1 presence conditions sufficient vessel density and the progression of vessel mimicry, which in short is unnecessary for the proper angiogenesis process. Another trial focused on lung cancer cells confirms that IDO1 activity is crucial for metastasis occurrence, and its inhibition improves patient outcomes
[56]. The described data point to mutual permeating of immunological processes and cancer development, as well as indicate IDO1 as a significant factor that takes part in this mechanism.