IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance

Abstract

Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.

Figure 1. The Tipping Point: is DNA sensed to impede or incite tumorigenesis?

A. During tumor growth DNA from dying cells is sensed by cGAS to stimulate STING/IFNαβ signaling, which potentiates immunogenic responses if tumors have relatively high antigenicity. These responses lead to tumor regression mediated by cytotoxic (CTL) and helper (Th) T cells. B. DNA is sensed to activate STING/IFNαβ signaling and induce IDO during tumorigenesis. IDO mediates dominant tolerogenic responses that activate Tregs to overcome immunogenic responses and promote tumorigenesis. These responses are more likely when tolerance thresholds are high due to low tumor antigenicity.

Figure 2. Effects of IDO exposure during Treg activation

During initial TCR-mediated activation of resting Tregs, signals via the Akt and mTOR pathways can potentially destabilize the Tregs and cause reprogramming into a pro-inflammatory helper-like phenotype (“ex-Tregs”). To prevent this, some signal must inhibit the mTOR/Akt axis during activation. If the antigen-presenting cell expresses IDO (e.g., due to up-regulation by apoptotic cells or other inflammatory signals) then this can inhibit mTORC2 signaling via a process mediated by low tryptophan and GCN2 kinase. In principle, depletion of other amino acids such as arginine (by local Arginase I) could create a similar GCN2-mediated inhibition of mTORC2. Potentially, other metabolic stresses in the tumor microenvironment might likewise affect mTORC1 and the feedback loop to mTORC2 and Akt. By whatever pathway, if Akt phosphorylation on the activating Ser473 residue is blocked, then the Treg is able to maintain expression of FoxO3a and acquire a highly suppressive phenotype that includes up-regulation of cell-surface PD-1 and the lipid phosphatase PTEN. PD-1 can signal via PTEN to inhibit PI3K activity, and thus block phosphorylation of the activating Thr308 residue on Akt. This self-sustaining feedback loop acts to stably maintain the inhibition of Akt long-term, even if the original IDO or other metabolic stress is removed. Neuropilin-1 (Nrp-1) can also activate PTEN, and thus may be able to establish a similar stable activation state in the Treg.

Figure 3. Potential model of tolerogenic versus immunogenic cell death in the tumor microenvironment

Tumor cells undergo a wave of cell death in response to chemotherapy, radiation or immunotherapy (e.g., T cell adoptive transfer, or other immunotherapy that activates cytotoxic T cells, CTLs). Some of the tumor cells may die via an immunogenic pathway that releases pro-inflammatory mediators such as HMGB1, ATP and STING. This immunogenic cell death has the potential to trigger inflammation, immunogenic cross-presentation of tumor antigens, and robust T cell activation. However, some fraction of the tumor cells also likely die by classical apoptosis, with consequent induction of immunosuppressive pathways such as TGFβ, IDO and IDO-induced pten-Treg activation. Unless the pro-inflammatory signals are very strong, these immunosuppressive signals (particularly activation of the potent pten-Tregs) are likely to be dominant. Thus, the net outcome of tumor cell death is often immune suppression and tolerance. Underneath, however, the immunogenic cell death may still be present, and available to drive anti-tumor immune responses if the dominant suppression is blocked.