Mansfield Aaron S, Heikkila Paivi S, Vaara Ari T, von Smitten Karl A J, Vakkila Jukka M, Leidenius Marjut H K
Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.
BMC Cancer. 2009 Jul 15;9:231. doi: 10.1186/1471-2407-9-231.
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.
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.
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.
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.
有证据表明乳腺癌患者的免疫系统功能失调。调节性T细胞（Tregs）以及吲哚胺2,3-双加氧酶（IDO，一种免疫抑制酶）在某些癌症中与更晚期疾病相关，并且可能促进对肿瘤的免疫耐受。我们的目的是评估Tregs标志物Foxp3的表达以及IDO是否与乳腺癌患者的淋巴结转移相关。IDO抑制剂已存在，如果IDO驱动疾病进展，那么其在乳腺癌中可能具有潜在效用。
采用免疫组织化学法评估47例具有不同程度淋巴结疾病的乳腺癌患者及10例对照者的前哨淋巴结（SLN）中Foxp3和IDO的表达。对阳性染色细胞进行定量，并记录其在前哨淋巴结内的分布情况。
癌症患者前哨淋巴结中Foxp3+细胞的比例高于对照组（19%对10%，p<0.001）。具体而言，有转移的前哨淋巴结中Foxp3+细胞比无肿瘤的前哨淋巴结更多（20%对14%，p = 0.02）。癌症患者前哨淋巴结中IDO+细胞的比例与对照组相比无统计学差异（4.0%对1.6%，p = 0.08）。为了证明Foxp3和IDO的联合免疫抑制作用，我们将每个前哨淋巴结按Foxp3和IDO阳性或阴性进行分类。Foxp3+/IDO+组几乎全部由淋巴结阳性疾病的癌症患者组成。
总之，我们的研究表明Foxp3+细胞与乳腺癌更晚期疾病相关，这一发现已在许多其他癌症中得到证实。由于已发现IDO可促进Tregs的分化，IDO可能成为消除T细胞耐受发展并促进对乳腺癌有效免疫反应的合适靶点。我们关于IDO和Foxp3在转移性前哨淋巴结中联合表达的结果支持这一假设。
