Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival

Abstract

The mechanism by which malignant melanoma (MM) cells survive in lymph nodes is poorly understood. One possible mechanism by which MM cells can escape immune surveillance is through upregulation of immunomodulatory enzymes such as indoleamine 2,3-dioxygenase (IDO). In this study, 25 cases of MM lymph node metastases from patients with long and short survival were evaluated for expression of IDO and the number of Forkhead box p3 (FOXP3)-expressing regulatory T cells. Moderate to strong cytoplasmic IDO expression was present in all (15/15) MM lymph node metastases in patients with poor survival. Eight of 10 patients with metastatic MM and long survival were negative or only weakly positive for IDO. Upregulation of IDO in metastatic MM cells was associated with an increased number of regulatory T cells (Tregs). There was a statistically significant association between shorter survival and both a stronger IDO expression (p = 0.0019) and a higher number of FOXP3 expressing Tregs (p < 0.001). Using RT-PCR analysis, we showed that IDO expression in MM cells is induced by interferon-gamma. These data support the notion that metastatic MM cells select for expression of IDO to evade immunologic detection. Therefore, inhibition of IDO in MM patients may be a useful treatment strategy.

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

“…Mature myeloid DCs are the most frequently cited (15)(16)(17), but IDO1 expression has also been reported in plasmacytoid DCs, immature DCs, and macrophages (18)(19)(20). Several studies have shown that IDO1 þ cells were enriched in melanoma-draining lymph nodes (18,(21)(22)(23). Some studies also reported a correlation between high IDO1 expression in TDLN and poor clinical outcome of melanoma, suggesting that IDO1 contributes to immune evasion (22)(23)(24).…”

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…An increased proportion of Ki67 + Tregs has been detected in multiple types of tumors, demonstrating their highly proliferative potential [30,48]. Finally, the upregulation of IDO in melanoma lymph node metastases has been associated with increased amounts of TITregs [49]. Accordingly, IDO expression by antigen-presenting cells (APCs) has been reported to directly activate Tregs and promote their proliferation [50,51].…”

CD13+CD4+CD25hiregulatory T cells exhibit higher suppressive function and increase with tumor stage in non-small cell lung cancer patients

“…[1][2][3][4][5][6][7][8][9] CD4 + CD25 + Treg cells are present in malignant effusions and blood 3,4,10 of individuals with various types of cancer, and suppress nonspecific T cell responses in vitro. Curiel and colleagues reported that Treg cells from ovarian carcinoma patients express functional CCR4 and traffic into tumor mass in response to chemokine CCL22 that is produced by tumor cells and microenvironmental macrophages.…”