ALC  Vol.2 No.4 , December 2013
Circulating IgG antibody against FOXP3 may be a potential biomarker for lung cancer
Abstract: Background: Forkhead box P3 (FOXP3) has been found to be overexpressed by a range of cancer cells and correlated with prognosis of tumors. This finding raises the possibility that the development of anti-FOXP3 antibody test may be useful for clinical application. Objective: The present work was designed to test whether circulating autoantibody to FOXP3 was altered in lung cancer. Methods: 271 patients with non-small cell lung cancer (NSCLC) and 227 in control subjects matched in age, gender and smoking history were recruited. Circulating anti-FOXP3 IgG antibody was tested using an in-house enzymelinked immunosorbent assay. Results: Student’s t-test showed that the levels of IgG autoantibody to FOXP3 were significantly higher in patients with NSCLC than control subjects (t = 7.67, P < 0.0001). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve (AUC) was 0.70 (95% CI 0.65 - 0.75, SE ± 0.024), in which patients at stage 2 had the highest AUC of 0.75 (95%CI 0.67 - 0.81, SE ± 0.037), with a sensitivity of 31.4% against a specificity of 90.3%. Analysis of quality control samples gave an inter-assay deviation of 13.3% among 45 plates tested. Conclusions: Circulating IgG autoantibody to FOXP3 may be a potential biomarker for lung cancer.
Cite this paper: Wang, W. , Ye, L. , Li, X. , Guan, S. , Sun, S. , Wang, M. , Guan, X. , Lee, K. , Wei, J. and Liu, B. (2013) Circulating IgG antibody against FOXP3 may be a potential biomarker for lung cancer. Advances in Lung Cancer, 2, 79-83. doi: 10.4236/alc.2013.24011.

[1]   Kobold, S., Lütkens, T., Cao, Y., Bokemeyer, C. and Atanackovic, D. (2010) Autoantibodies against tumorrelated antigens: Incidence and biologic significance. Human Immunology, 71, 643-651.

[2]   Jaras, K. and Anderson, K. (2011) Autoantibodies in cancer: Prognostic biomarkers and immune activation. Expert Review of Proteomics, 8, 577-589.

[3]   Liu, W., Peng, B., Lu, Y. Xu, W., Qian, W. and Zhang, J.-Y. (2011) Autoantibodies to tumor-associated antigens as biomarkers in cancer immunodiagnosis. Autoimmunity Reviews, 10, 331-335.

[4]   Piura, E. and Piura, B. (2010) Autoantibodies to tumorassociated antigens in breast carcinoma. Journal of Oncology, 2010, 264926.

[5]   Piura, E. and Piura, B. (2011) Autoantibodies to tailormade panels of tumor-associated antigens in breast carcinoma. Journal of Oncology, 2011, 982425.

[6]   Zhong, L., Coe, S.P., Stromberg, A.J., Khattar, N.H., Jett, J.R. and Hirschowitz, E.A. (2006) Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. Journal of Thoracic Oncology, 1, 513-519.

[7]   Chapman, C., Murray, A., Chakrabarti, J., Thorpe, A., Woolston, C., Sahin, U., Barnes, A. and Robertson, J. (2007) Autoantibodies in breast cancer: Their use as an aid to early diagnosis. Annals of Oncology, 18, 868-873.

[8]   Tan, H.T., Low, J., Lim, S.G. and Chung, M.C. (2009) Serum autoantibodies as biomarkers for early cancer detection. FEBS Journal, 276, 6880-6904. 07396.x

[9]   Chapman, C.J., Healey, G.F., Murray, A., Boyle, P., Robertson, C., Peek, L.J., Allen, J., Thorpe, A.J., Hamilton-Fairley, G., Parsy-Kowalska, C.B., MacDonald, I.K., Jewell, W., Maddison, P. and Robertson, J.F. (2012) EarlyCDT?-Lung test: Improved clinical utility through additional autoantibody assays. Tumor Biology, 33, 1319-1326.

[10]   Coffer, P.J. and Burgering, B.M. (2004) Forkhead-box transcription factors and their role in the immune system. Nature Reviews Immunology, 4, 889-899.

[11]   Redpath, M., Xu, B., van Kempen, L.C. and Spatz, A. (2011) The dual role of the X-linked FoxP3 gene in human cancers. Molecular Oncology, 5, 156-163.

[12]   Olkhanud, P.B., Damdinsuren, B., Bodogai, M., Gress, R.E., Sen, R., Wejksza, K., Malchinkhuu, E., Wersto, R.P. and Biragyn, A. (2011) Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Research, 71, 3505-3515.

[13]   Ebert, L.M., Tan, B.S., Browning, J., Svobodova, S., Russell, S.E., Kirkpatrick, N., Gedye, C., Moss, D., Ng, S.P., MacGregor, D., Davis, I.D., Cebon, J. and Chen, W. (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Research, 68, 3001-3009.

[14]   Karanikas, V., Speletas, M., Zamanakou, M., Kalala, F., Loules, G., Kerenidi, T., Loules, G., Kerenidi, T., Barda, A.K., Gourgoulianis, K.I. and Germenis, A.E. (2008) Foxp3 expression in human cancer cells. Journal of Translational Medicine, 6, 19.

[15]   Yoshii, M., Tanaka, H., Ohira, M., Muguruma, K., Iwauchi, T., Lee, T., Sakurai, K., Kubo, N., Yashiro, M., Sawada, T. and Hirakawa, K. (2012) Expression of Forkhead box P3 in tumour cells causes immunoregulatory function of signet ring cell carcinoma of the stomach. British Journal of Cancer, 106, 1668-1674.

[16]   Triulzi, T., Tagliabue, E., Balsari, A. and Casalini, P. (2013) FOXP3 expression in tumor cells and implications for cancer progression. Journal of Cellular Physiology, 228, 30-35. 1002/jcp.24125

[17]   Wang, P., Sidney, J., Kim, Y., Sette, A., Lund, O., Nielsen, M., Nielsen, M. and Peters, B. (2010) Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinformatics, 11, 568.

[18]   Ye, L., Guan, S., Zhang, C., Lee, K-H., Sun, L., Wei, J. and Liu, B. (2013) Circulating autoantibody to FOXP3 may be a potential biomarker for esophageal squamous cell carcinoma. Tumor Biology, 34, 1873-1877.

[19]   Ye, L., Li, X., Sun, S., Guan, S., Wang, M., Guan, X., Lee, K-H., Wei, J. and Liu, B. (2013) A study of circulating anti-CD25 antibodies in non-small cell lung cancer. Clinical and Translational Oncology, 5, 633-637.

[20]   Zuo, T., Wang, L., Morrison, C., Chang, X., Zhang, H., Li, W., Wang, L., Zheng, P. and Liu, Y (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell, 129, 1275-1286.

[21]   Wang, L., Liu, R., Li, W., Chen, C., Katoh, H., Chen, G.Y., McNally, B., Lin, L., Zhou, P., Zuo, T., Cooney, K.A., Liu, Y. and Zheng, P. (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell, 16, 336-346.

[22]   Chen, Y.T., Scanlan, M.J., Sahin, U., Türeci, O., Gure, A.O. and Tsang, S. (1997) A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proceedings of the National Academy of Sciences, 94, 1914-1918.

[23]   Mayerhofer, K., Tempfer, C., Kucera, E., Hefler, L., Zeisler, H., Kainz, C., Zeillinger, R. and Sliutz, G. (1999) Humoral p53 antibody response is a prognostic parameter in ovarian cancer. Anticancer Research, 19, 875-878.

[24]   Abendstein, B., Daxenbichler, G. and Windbichler, G. (2000) Predictive value of uPA, PAI-1, HER-2 and VEGF in the serum of ovarian cancer patients. Anticancer Research, 20, 569-572.

[25]   Goodell, V., Salazar, L.G., Urban, N., Drescher, C.W., Gray, H., Swensen, R.E., McIntosh, M.W. and Disis, M.L. (2006) Antibody immunity to the p53 oncogenic protein is a prognostic indicator in ovarian cancer. Journal of Clinical Oncology, 24, 762-768.

[26]   Anderson, K.S., Wong, J., Vitonis, A., Crum, C.P., Sluss, P.M., Labaer, J., Cramer, D. and Cramer, D. (2010) p53 autoantibodies as potential detection and prognostic biomarkers in serous ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention, 19, 859-868. -9965.EPI-09-0880

[27]   Wolf, A.M., Rumpold, H., Wolf, D., Gastl, G., Reimer, D., Jenewein, N., Marth, C. and Zeimet, A.G. (2007) Role of forkhead box protein 3 expression in invasive breast cancer. Journal of Clinical Oncology, 25, 4499-4500.

[28]   Deleeuw, R.J., Kost, S.E., Kakal, J.A. and Nelson, B.H. (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: A critical review of the literature. Clinical Cancer Research, 18, 3022-3029.

[29]   Wang, G., Liu, G., Liu, Y., Li, X. and Su, Z. (2012) FOXP3 expression in esophageal cancer cells is associated with poor prognosis in esophageal cancer. Hepatogastroenterology, 59, 2186-2191.

[30]   Tao, H., Mimura, Y., Aoe, K., Kobayashi, S., Yamamoto, H., Matsuda, E., Okabe, K., Matsumoto, T., Sugi, K. and Ueoka, H. (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer, 75, 95-101. 10.1016/j.lungcan.2011.06.002