Pattern of Recruitment of Immunoregulatory Antigen-Presenting Cells in Malignant Melanoma

Abstract

SUMMARY:The mechanism by which the immune system of a tumor-bearing host acquires tolerance toward tumor antigens is still elusive. Antigen-presenting cells (APCs) are critical regulators of the decision between immune response and tolerance. APCs that express the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) have been found to inhibit T-cell responses both in vitro and in vivo. We hypothesized that malignant tumors exploit this mechanism by recruiting IDO-expressing APCs to the tumor-draining lymph nodes. To test this hypothesis, archival tissues and records of 26 cases of lymph node dissection for invasive cutaneous melanoma were obtained. IDO immunohistochemistry was performed on 14 cutaneous tumors and 328 regional lymph nodes. Abnormal accumulations of IDO-positive cells with a monocytoid or plasmacytoid morphology were identified in the perisinusoidal regions of draining lymph nodes in 45% of nodes studied. Recruitment of IDO-positive cells was seen in nodes with and without malignancy. We hypothesize that these IDO-positive APCs may contribute mechanistically to acquired tolerance to tumor antigens. Immunostaining of tumor-draining lymph nodes for abnormal accumulation of IDOexpressing cells might thus constitute an adverse prognostic factor and could contribute to the decision process and the appropriate care of patients with this deadly disease. (Lab Invest 2003, 83:1457-1466.

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

“…We selected TDLNs from 15 patients with melanoma and 15 patients with breast carcinoma, whose characteristics are described in Supplementary Table S2, and are comparable with previous reported work (21). IDO1 þ cells were present in the TDLNs, but their numbers were not different from those observed in normal lymph nodes, as estimated by the relative area occupied by IDO1 þ cells (Fig.…”

“…Similar results were obtained with an in-house rabbit polyclonal anti-IDO1 antibody. However, a rabbit antiserum (AB5968 from Chemicon International), previously used to assess IDO1 expression in DCs and in placenta (18,21), stained an additional band both in IDO1-positive and IDO1-negative cells, indicating a lack of specificity. Consistent results were obtained with IHC ( Supplementary Fig.…”

“…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).…”

“…S1; refs. 18,21,22 using either LPS or a cocktail of IL1b, IL6, TNFa, and PGE2, commonly used to produce DC-based vaccines for clinical immunotherapy. As reported previously by others, iDCs did not express IDO1, whereas both types of mature DCs did (Supplementary Fig.…”

Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

“…However, a prominent population of IDO-expressing cells is observed in many human TDLNs (40), displaying a characteristic plasmacytoid morphology (41). Recently, human plasmacytoid DCs (CD123 + BDCA2 + ) have been shown to upregulate IDO in response to HIV infection (42); thus, authentic human pDCs can be induced to express IDO.…”