Regulation of the Immune Checkpoint Indoleamine 2,3-Dioxygenase Expression by Epstein-Barr Virus

Abstract

Epstein-Barr virus (EBV) is an oncovirus ubiquitously distributed and associated with different types of cancer. The reason why only a group of infected people develop cancer is still unknown. EBV-associated cancers represent about 1.8% of all cancer deaths worldwide, with more than 150,000 new cases of cancer being reported annually. Since EBV-associated cancers are described as more aggressive and more resistant to the usual treatment compared to EBV-negative ones, the recent introduction of monoclonal antibodies (mAbs) targeting immune checkpoints (ICs) in the treatment of cancer patients represents a possible therapy for EBV-associated diseases. However, the current mAb therapies available still need improvement, since a group of patients do not respond well to treatment. Therefore, the main objective of this review is to summarize the progress made regarding the contribution of EBV infection to the expression of the IC indoleamine 2,3-dioxygenase (IDO) thus far. This IC has the potential to be used as a target in new immune therapies, such as mAbs. We hope that this work helps the development of future immunotherapies, improving the prognosis of EBV-associated cancer patients.

Keywords: Epstein–Barr virus; immune checkpoints; indoleamine 2,3-dioxygenase.

Figure 1

Proposed mechanism of the IDO-specific contribution to immunosuppression in EBV(−) cancer and EBV(+) cancer. (A) During homeostasis, CTLs utilize tryptophan in order to eliminate cancer cells. The degradation of tryptophan generates Kyn, which negatively contributes to NKG2D regulation of expression in NK cells. (B) EBV has been reported to increase IDO expression in infected cells; therefore, Trp degradation is enhanced, and so is Kyn accumulation. As a result, a more significant immunosuppression status is established, since CTL responses are inhibited, and stronger inhibition of NKG2D in NK cells can be observed. In addition, MIC-A, a NKG2D ligand, has been reported to be downregulated in EBV-infected cancer cells through the TGF-β/c-myc pathway. In this model, the activation of the RIG-I pathway through EBER1, delivered by exosomes, directly regulates IDO expression in cancer cells and/or also activates the NF-kB pathway in them, inducing the production of TNF-α and IL-6, culminating in the upregulation of IDO. The increased IDO expression in cancer cells would exacerbate the immunosuppression by increasing Trp utilization and Kyn accumulation. IL-27 would also play a role in this scenario, contributing to the expression of both IDO and PD-L1; the latter IC receptor expression, PD-1, increases on CD8⁺T cells as Kyn accumulates in the microenvironment. The use of specific IDO inhibitors would have a greater impact on EBV-associated malignancies, since IDO expression is higher when compared to EBV(−) cases. Thick lines represent stronger activation/expression than thin lines (weaker activation/expression). EBV: Epstein–Barr virus; CTL: cytotoxic T cell; JAK3/STAT3: Janus-kinase-3/signal transducer and activator of transcription-3; KYN: kynurenine; MAPK: mitogen-activated protein kinase; MIC-A: MHC class I polypeptide-related sequence A; NF-κB: nuclear factor-κB; NKG2D: NKG2-D type II integral membrane protein; PD-1: programmed cell death protein; PD-L1: programmed death-ligand 1; TGF-β/c-myc: transforming growth factor β/c-myc; TRP: tryptophan.