Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation

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Tumors create an abnormal state of tolerance toward themselves and their antigens. One mechanism that might contribute to this tolerance is the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO-expressing antigen-presenting cells are found in tumor-draining lymph nodes, where they can create a tolerogenic microenvironment. IDO can also be expressed within the tumor itself, by tumor cells or host stromal cells, where it can inhibit the effector phase the immune response. Finally, emerging evidence suggests that IDO might also constitute a significant counter-regulatory mechanism, induced by clinically relevant pro-inflammatory signals, such as IFN-γ, IFN-α, CpG oligodeoxynucleotides, and 4-1BB ligation. Strategies to inhibit the IDO pathway may thus assist in breaking tolerance to tumors, and might enhance the efficacy of other immunotherapy strategies by removing unwanted counter-regulation.

Introduction

The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) can be a potent mechanism of immunosuppression and tolerance induction in certain settings. In vitro and in vivo studies of IDO and its general role in the immune system have been recently reviewed [1]. The specific focus of the current discussion is the ways in which IDO functions in the context of tumor immunology. I will consider IDO in two potential roles: first, as a primary molecular target for cancer immunotherapy; and second, as an endogenous counter-regulatory mechanism that can secondarily antagonize the effectiveness of other immunotherapy strategies.

Section snippets

IDO and tolerance

The biological role of IDO in the immune system is still a subject of active investigation. Endogenous IDO has been implicated as one mechanism that helps maintain maternal tolerance toward the fetus [2]. This may be conceptually relevant to tumor immunology, as the fetus constitutes a large set of new antigens to which the immune system acquires tolerance [3]. IDO also regulates the severity of a variety of experimental autoimmune disorders [4, 5, 6, 7]. IDO does not, however, appear to be

Tumors exploit natural tolerogenic mechanisms

It seems unlikely that tumors would independently evolve completely novel molecular mechanisms to evade the immune system. Rather, just as the tumor co-opts preexisting host mechanisms to grow new blood vessels and perform other complex tasks, it is likely that the tumor subverts natural host mechanisms (such as IDO) to create tolerance to itself. In considering where these mechanisms might operate, it is helpful to distinguish between regulation of the afferent (priming) arm of the immune

Stochastic activation of the IDO system in tumor-bearing hosts

The two roles for IDO described above — inhibition of afferent and efferent immune responses — are not mutually exclusive, and both could operate in a given tumor. The tumor's ability to elicit IDO-mediated immune suppression (or not) presumably reflects a stochastic process of acquired mutations, driven by selection pressure from the host immune system. In this regard, it is interesting to note recent results from Muller and colleagues [24••], using a spontaneous mouse breast-tumor model (the

Use of IDO inhibitor drugs in combination therapy regimens

Although IDO may be involved in tolerance and immunosuppression in tumor-bearing hosts, it is certainly not the only mechanism participating in these processes. In the case of tolerance in particular, when the tolerant state has been acquired the role of IDO may be over (i.e. the ongoing condition of tolerance can be maintained by other mechanisms). Thus, in the setting of an established tumor, simply inhibiting IDO is not likely to be sufficient, by itself, to break tolerance. From a practical

IDO as a counter-regulatory mechanism

The preceding discussion has focused on IDO expression related to the tumor: either IDO expressed by tumor cells themselves, or IDO expressed by host cells in response to the tumor. However, there is an additional role in which IDO may be relevant to the clinical immunotherapy of cancer, and that is as an inflammation-induced counter-regulatory mechanism.

Counter-regulatory responses are important in the immune system: they help to limit the intensity and extent of strong immune responses, which

Conclusions

Much remains to be learned about the biology of IDO in general, and its role in tumor immunology in particular. The fact that IDO is frequently expressed in tumors and TDLNs, combined with its potent immunosuppressive activity in certain settings, certainly warrants further investigation. Clinically, it is encouraging that there are orally bioavailable small-molecule inhibitor drugs available to target this pathway. Finally, the fact that IDO appears to be secondarily induced by several other

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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