Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer

Abstract

BackgroundThere is evidence that the immune systems of patients with breast cancer are dysfunctional. Regulatory T cells (Tregs), and IDO, an immunosuppressive enzyme, are associated with more advanced disease in some cancers and may promote immunologic tolerance to tumors. Our aim was to assess whether expression of Foxp3, a marker of Tregs, and IDO were linked with nodal metastasis in breast cancer patients. Inhibitors of IDO are available and could potentially demonstrate utility in breast cancer if IDO drives progression of disease.MethodsSentinel lymph nodes (SLN) of 47 breast cancer patients with varying degrees of nodal disease and 10 controls were evaluated for expression of Foxp3 and IDO using immunohistochemistry. Positively stained cells were quantified and their distribution within the SLN noted.ResultsThe proportion of Foxp3+ cells was higher in SLN of cancer patients than controls (19% v. 10%, p < 0.001). Specifically, there were more Foxp3+ cells in SLN with metastasis than tumor-free SLN (20% v. 14%, p = 0.02). The proportion IDO+ cell in SLN of cancer patients was not statistically different than controls (4.0% v. 1.6%, p = 0.08). In order to demonstrate the combined immunosuppressive effect of Foxp3 and IDO, we categorized each SLN as positive or negative for Foxp3 and IDO. The Foxp3+/IDO+ group almost exclusively consisted of cancer patients with node positive disease.ConclusionIn conclusion, our study shows that Foxp3+ cells are associated with more advanced disease in breast cancer, a finding that is proving to be true in many other cancers. As IDO has been found to promote differentiation of Tregs, IDO may become a suitable target to abrogate the development of T-cell tolerance and to promote an effective immune response to breast cancer. Our results about the combined expression of IDO and Foxp3 in metastastic SLN support this assumption.

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

“…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). However, another study performed in breast cancer did not show an enrichment of IDO1 þ cells in TDLN (25).…”

Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases

“…FOXP3 expression is associated with significantly worse prognosis in node-positive BC (17). Members of our group earlier found significantly higher FOXP3 positivity in T-lymphocytes in metastatic sentinel nodes (SNs) than in tumor-free SNs, indicating local immunosupression mediated by Treg activation (18).…”

Prostanoid induces premetastatic niche in regional lymph nodes

“…Mansfield et al reported that FOXP3 + cells were associated with more advanced disease in breast cancer, a finding that is proven to be true in many other cancers (54). DCs have been found to promote Treg differentiation and may become a suitable target to abrogate the development of T cell tolerance and to promote an effective immune response to breast cancer (54). As shown in Figure 5B, the recruitment of Tregs was observed in the regional lymph node premetastatic niche, and it was suppressed by COX-2 inhibition, EP3 blockade, and SDF-1 blockade.…”

“…Tregs were selectively recruited within lymphoid infiltrates and activated by mature DCs, likely through the recognition of tumor-associated antigen presentation, resulting in the prevention of effector T cell activation, immune escape, and, ultimately, tumor progression (53). Mansfield et al reported that FOXP3 + cells were associated with more advanced disease in breast cancer, a finding that is proven to be true in many other cancers (54). DCs have been found to promote Treg differentiation and may become a suitable target to abrogate the development of T cell tolerance and to promote an effective immune response to breast cancer (54).…”