The specific targeting of immune regulation: T-cell responses against Indoleamine 2,3-dioxygenase

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in many settings including cancer. In recent years, we have described spontaneous CD8(+) as well as CD4(+) T-cell reactivity against IDO in the tumor microenvironment of different cancer patients as well as in the peripheral blood of both cancer patients and to a lesser extent in healthy donors. We have demonstrated that IDO-reactive CD8(+) T cells were peptide-specific, cytotoxic effector cells, which are able to recognize and kill IDO-expressing cells including tumor cells as well as dendritic cells. Consequently, IDO may serve as a widely applicable target for immunotherapeutic strategies with a completely different function as well as expression pattern compared to previously described antigens. IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, and IDO-based immunotherapy may consequently be synergistic with additional immunotherapy. In this regard, we have shown that the presence of IDO-specific T cells boosted immunity against CMV and tumor antigens by eliminating IDO(+) suppressive cells and changing the regulatory microenvironment. The current review summarizes current knowledge of IDO as a T-cell antigen, reports the initial results that are suggesting a general function of IDO-specific T cells in immunoregulation, and discusses future opportunities.

Trial registration: ClinicalTrials.gov NCT01219348.

Fig. 1

Principle of the processing pathway of IDO peptides by IDO-expressing cells (red), for example, tumor cells or dendritic cells and the subsequent recognition by specific CD8 T cells (green; here entitled a “supporter T cell” (Tsup).The epitopes recognized by the T cells are short IDO-derived peptides resulting from the degradation of intracellular IDO protein, which are presented on the cell surface of HLA molecules. T cells receive an activation signal through their T-cell receptor complex, leading to a variety of functional consequences, including release of cytokines and cytotoxic molecules

Fig. 2

IDO-specific T cells are able to boost specific immunity against virus or tumor antigens in human PBMC. a When stimulating PBMC with a known HLA-restricted T-cell virus epitope and IL-2, epitope-specific T cells begin to expand due to activation by antigen presenting cells (APC). In response to the subsequent production of cytokines like INF-γ, IDO expression is induced and IDO-expressing APC inhibit further expansion of virus-specific T cells both directly and indirectly through activation of Tregs. b The addition of cytotoxic, IDO-specific T cells (Tsup) removes immune suppressive cells from the PBMC culture thereby facilitating further expansion of virus-specific T cells

Fig. 3

Vaccine induced IDO-specific T cells might kill IDO⁺ suppressive antigen presenting cells (APC) as well as IDO⁺ cancer cells both at the tumor site and in the draining lymph nodes. IDO may exhibit its immune inhibitory functions both in the activation phases (in the draining lymph node) as wells as in the effector phases (at the site of the tumor). Hence, an IDO-based cancer vaccine might work directly at the tumor site by the attack of cancer cells as well as stromal cells as well as in the draining lymph node by the attack of IDO-expressing regulatory cells