7.4.3 IDO-induced Tumor Immune Escape
Expression of IDO by cancer cells as well as by APCs have been detected in the tumor infiltrating zone, in the peritumoral stroma and in tumor-draining lymph nodes.Human tumor tissues of lung,prostatic, pancreatic, cervical and other origins have been examined, demonstrated that IDO was expressed at variable levels.In all cases most normal cells of the stroma were negative, suggesting that IDO expression by tumor cells did not result from in vivo exposure to IFN-.We have observed that in tumor tissue material resected from patients with various forms of lung cancer, the expression of IDO was higher than that detected in the adjacent non-affected lung tissue.This result is in accordance with similar findings of other investigators regarding the ability of other types of cancer cells, such as colon cancer, ovarian cancer, breast cancer, etc., to produce this immunoregulatory enzyme.IDO expression, has been utilized by several investigators examining tumor types other than lung cancer as a correlative clinicopathological marker with prognostic significance.
IDO expression within the tumoral environment, irrespective of the producing cell, could result in evasion of immune mediated rejection of tumor cells.In fact, in non-small cell lung adenocarcinoma, tumor infiltrating eosinophils appear to be solely responsible for the occurrence of an IDO-dependent immunosuppression.It was also observed that tumor progression was accelerated in patients displaying a large amount of these cells in the inflammatory infiltrate,suggesting that IDO-expressing granulocytes might be used as a prognostic marker.Moreover, the expression of IDO by immunogenic mouse tumor cells prevented their rejection by preimmunized mice.This effect was accompanied by a lack of accumulation of specific T cells at the tumor site and was partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity.
Two downstream mechanisms, both within the context of a tryptophan depleted environment, could explain how the expression of IDO by tumor cells or by host’s APCs and tumor infiltrating cells,shields the tumor from an immune response against it.The first refers to a direct suppression of T cell function and/or expansion and the second to effects imposed upon T cells by tumor infiltrating APC.With respect to the former, it is considered that tumor cells utilize IDO in order to escape immune surveillance, by sharing similar mechanisms to those recruited in either maintaining maternal tolerance or contributing to the induction of T cell acceptance of mismatched allografts in animal models of disease.With respect to the role of IDO-expressing APC, their presence within the tumor microenvironment appears to utilize tryptophan to such a critical level that it could inhibit T cell activation.It was identified that monocyte-derived macrophages express two types of receptors implicated in the intracellular transport of tryptophan, a high and a low affinity one.The former was induced upon monocyte differentiation and this could provide the necessary starving environment for diminished T cell function and expansion.In vitro, the critical level of tryptophan concentration for T cell proliferation was found to be around 1-2μM [60].Any deviation from this did not allow T cells to transit into S phase, interfering therefore with their clonal amplification.This suggests that T cells have a sensitive mid-G1 cell cycle checkpoint that inhibits their transition to further cellular processes.Other cell types, however, including tumor cells would be able to maintain their growth ability even in the presence of lower levels of tryptophan.It is therefore possible that tumor cells can survive in an immunocompetent host by selectively recruiting IDO producing APCs.(https://www.daowen.com)
Within the tumoral environment, the role that natural killer cells (NK) play against tumor eradication cannot be overlooked.Through the effects observed on the proliferation of T cells and NK in the presence of IDO, the latter were also identified to express this molecule.The biological significance of this expression by NK, was realized even further, when IDO was found to play an important role in compromising anti-tumor immunity by regulating cytotoxic activity of NK cells.Together with the finding that HLA-G molecules and IDO can be co-expressed and both can be induced as a response to proinflammatory molecules, it becomes apparent than this can be utilized as an added mechanism to mediate tumor immune escape from T cell recognition and destruction.
Beyond the tryptophan depletion, accumulation of IDO metabolites into the tumor environment seems to also propagate the suppression of anti-tumor immune responses.As discussed earlier, the catabolism of tryptophan results in N-formyl-kynurenine and many downstream metabolites, such as 3-hydroxyanthranilic acid, kynurenate and quinolinate.It seems that, after immune stimulation,these metabolites increase in the blood and in various tissues being quite detrimental especial for the T cell, inducing both their anergy and death.For instance, the presence of 3-hydroxyanthranilic acid and kynurenate in low doses does not affect the ability of T cells to respond to antigenic stimulation but it rather severely interferes with antigen independent stimulation through growth factor binding to receptors sharing a common γ chain.The effects were more prominent for 3-hydroxyanthranilic acid and to a lesser extent for kynurenate.However, when the concentration of these metabolites is increased at least 10-fold, then CD8+ T cell apoptosis does take place.Moreover, alloantigen or mitogen stimulated T cell proliferation is inhibited when tryptophan metabolites are present at high concentrations (＞100 μM).This detrimental effect of IDO metabolites has also been observed to impair NK cellular cytotoxicity by particularly targeting the expression of key NK receptors involved in target recognition.Although L-kynurenine was the metabolite used in these studies at concentrations similar to those observed in vitro models , the most important message seems to be that that the tumoral microenvironment remains the ground upon which effective anti-tumor immune responses can be affected by a fine balance in the concentration of a plethora of soluble factors.
Since many points of the afore mentioned mechanisms of local function of IDO remain unclarified,a question emerges about the possibility of IDO to promote tumor immune escape acting at a systemic level.Evidence towards this option stems from recent work linking the presence of tryptophan and the induction of an immunoregulatory or an anergic T cell phenotype.T cells activated in the presence of IDO-expressing DCs begin to express a GCN2 kinase-dependent integrated stress response (ISR).Since the activation of this kinase relies on increased levels of tryptophan-tRNA, essential for protein synthesis, any alterations could provide the signal to T cells to undergo differentiation, apoptosis or even cell cycle arrest [68].These T cells could travel to distal sites, such as those of metastases, and remain non-responsive despite expressing appropriate anti TA-TcRs.In support of this possibility, recent data indicating that CTLA4 present on T cells could activate a signaling pathway leading to the induction of IDO expression by DCs, suggests that T cells could interfere with responses of other cells without the need for direct contact.