Foxp3 expression is associated with aggressiveness in differentiated thyroid carcinomas

Abstract

OBJECTIVES:Forkhead box P3 (FoxP3) expression has been observed in human cancer cells but has not yet been reported in thyroid cells. We investigated the prognostic significance of both FoxP3 expression and intratumoral FoxP3+ lymphocyte infiltration in differentiated thyroid carcinoma cells.METHODS:We constructed a tissue microarray with 385 thyroid tissues, including 266 malignant tissues (from 253 papillary thyroid carcinomas and 13 follicular carcinomas), 114 benign lesions, and 5 normal thyroid tissues.RESULTS:We determined the expression of FoxP3 in both tumor cells and tumor-infiltrating lymphocytes using immunohistochemical techniques. Cellular expression of FoxP3 was evident in 71% of benign and 91.9% of malignant tissues. The nuclear and cytoplasmic expression patterns were quantified separately. A multivariate logistic regression analysis indicated that cytoplasmic FoxP3 expression is an independent risk factor for thyroid malignancy. Cytoplasmic FoxP3 staining was inversely correlated with patient age. Nuclear FoxP3 staining was more intense in younger patients and in tumors presenting with metastasis at diagnosis. FoxP3+ lymphocytes were more frequent in tumors smaller than 2 cm, those without extrathyroidal invasion, and in patients with concurrent chronic lymphocytic thyroiditis.CONCLUSIONS:We demonstrated FoxP3 expression in differentiated thyroid carcinoma cells and found evidence that this expression may exert an important influence on several features of tumor aggressiveness.

Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells

“…Similar to most other types of human cancers, Foxp+ Tregs in either peripheral blood or tumor tissues of human thyroid cancer are increased, compared with blood and tissue samples from normal subjects or those with thyroid nodular goiter (Cunha et al, 2012;French et al, 2010;Gogali et al, 2012;Muller et al, 2010;Szylberg et al, 2014;Yu et al, 2013), which is confirmed in thyroid cancer tissues and matched non-cancer tissues used in this study (Appendix: Supplementary Fig. S1).…”

“…There are several studies showing that the expression of Foxp3+ Tregs is increased in the peripheral blood and/or cancer tissues of PTC, FTC and medullary thyroid carcinoma (MTC) and that the increased levels of Foxp+ Tregs are associated with a more aggressive form of the cancer and/ or poor clinical prognosis (French et al, 2010;Gogali et al, 2012;Muller et al, 2010;Yu et al, 2013). Very limited information is available for the expression of Foxp3 in thyroid cancer cells, as there are only three reports indicating that thyroid cancer cells of PTC and FTC express Foxp3 which is associated with tumor aggressiveness and resistance to radioiodine treatment (Cunha et al, 2012;Szylberg et al, 2014;Ugolini et al, 2014). Although the function of Foxp3 expressed in thyroid cancer cells remains unexplored, the available data seem to suggest a pro-tumor growth role of Foxp3.…”

FOXP3 autoantibody as a potential early prognostic serum biomarker in patients with cervical cancer

“…Immune surveillance is one of the most basic functions of the immune system; it can identify, destroy, kill or inhibit The theory also provides a way for the early detection of cancer [17]. When patients have not presented any symptoms and their TAAs are at low level, the immune system is able to monitor the presence of TAAs and cause immune responses, producing large amounts of autoantibodies to clear carcinomic antigens.…”

Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

“…B7H1 expression was associated with the presence of a mixture of immune cells infiltrating tumor samples including FOXP3C lymphocytes, which we recently demonstrated associated with DTC features of aggressiveness (Cunha et al 2012b). These lymphocytes may provoke a molecular mimicry that enables immune evasion (Hinz et al 2007) and modulates patterns of molecule expression in tumor cells, thus favoring an aggressive phenotype (Merlo et al 2009).…”

“…Each spot is assessed in triplicate and the final value is given by the mean of triplicates, as previously reported (Minot et al 2009, Morari et al 2010. Aiming to perform survival analysis, staining %median was considered negative and staining Omedian was considered positive, as described previously (Cunha et al 2012b).…”