Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer - PubMed (original) (raw)

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

Aaron S Mansfield et al. BMC Cancer. 2009.

Abstract

Background: There 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.

Methods: Sentinel 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.

Results: The 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.

Conclusion: In 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.

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Figures

Figure 1

Figure 1

Foxp3 and IDO expression in the sentinel lymph nodes (SLN). This figure illustrates the expression of IDO (top row) and Foxp3 (bottom row) in a SLN with a 7 mm breast cancer metastasis at 100× (first column), and 400× (second column) magnification. Foxp3+ cells are located primarily in the paracortical regions, whereas IDO+ cells infiltrate perisinusoidal areas. The pericapsular fat is marked by the circle, the paracortex by the diamond, the marginal sinus by the arrowhead, and the medullary sinus by the diamond.

Figure 2

Figure 2

Foxp3 and IDO expression in the sentinel lymph nodes of breast cancer patients and controls. The expression of Foxp3 is shown as the median percentage of positive cells in the sentinel lymph nodes of breast cancer patients and controls (a), and of node-positive, node-negative breast cancer patients and controls (b). The expression of IDO is shown as the median percentage of positive cells in the sentinel lymph nodes of breast cancer patients and controls (c), and of node-positive, node-negative breast cancer patients and controls (d).

Figure 3

Figure 3

Correlation of the infiltration of Foxp3+ and IDO+ cells. The correlation of Foxp3 and IDO expression of controls (a), node-negative (b), and node-positive (c) patients is graphed above. There were significant correlations in the expression of both markers between the sentinel lymph nodes of the controls (p = 0.04) and those of patients with tumor-free sentinel lymph nodes (p = 0.003).

Figure 4

Figure 4

Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer. In order to demonstrate the combined immunosuppressive effect of Foxp3 and IDO, we categorized each subject into one of four groups based on whether positive or negative for Foxp3 and IDO. The median proportion of Foxp3+ and IDO+ cells in the SLN in cancer patients were used the cut-off points. Subjects who were positive both for Foxp3 and IDO were almost exclusively those with nodal disease, (p = 0.007).

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