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Cancer-associated mucins: role in immune modulation and metastasis

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Abstract

Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.

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References

  1. Kaur, S., Kumar, S., Momi, N., Sasson, A. R., & Batra, S. K. (2013). Mucins in pancreatic cancer and its microenvironment. Nature Reviews. Gastroenterology & Hepatology, 10(10), 607–620. https://doi.org/10.1038/nrgastro.2013.120.

    Article  CAS  Google Scholar 

  2. Moniaux, N., Andrianifahanana, M., Brand, R. E., & Batra, S. K. (2004). Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy. British Journal of Cancer, 91(9), 1633–1638. https://doi.org/10.1038/sj.bjc.6602163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lakshmanan, I., Rachagani, S., Hauke, R., Krishn, S. R., Paknikar, S., Seshacharyulu, P., et al. (2016). MUC5AC interactions with integrin beta4 enhances the migration of lung cancer cells through FAK signaling. Oncogene, 35(31), 4112–4121. https://doi.org/10.1038/onc.2015.478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lakshmanan, I., Seshacharyulu, P., Haridas, D., Rachagani, S., Gupta, S., Joshi, S., et al. (2015). Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells. Oncotarget, 6(25), 21085–21099. https://doi.org/10.18632/oncotarget.3912.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chaturvedi, P., Singh, A. P., Chakraborty, S., Chauhan, S. C., Bafna, S., Meza, J. L., et al. (2008). MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Research, 68(7), 2065–2070. https://doi.org/10.1158/0008-5472.Can-07-6041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ramasamy, S., Duraisamy, S., Barbashov, S., Kawano, T., Kharbanda, S., & Kufe, D. (2007). The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Molecular Cell, 27(6), 992–1004. https://doi.org/10.1016/j.molcel.2007.07.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Senapati, S., Chaturvedi, P., Chaney, W. G., Chakraborty, S., Gnanapragassam, V. S., Sasson, A. R., et al. (2011). Novel INTeraction of MUC4 and galectin: potential pathobiological implications for metastasis in lethal pancreatic cancer. Clinical Cancer Research, 17(2), 267–274. https://doi.org/10.1158/1078-0432.Ccr-10-1937.

    Article  CAS  PubMed  Google Scholar 

  8. Chen, S. H., Hung, W. C., Wang, P., Paul, C., & Konstantopoulos, K. (2013). Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Scientific Reports, 3, 1870. https://doi.org/10.1038/srep01870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brockhausen, I. (1999). Pathways of O-glycan biosynthesis in cancer cells. Biochimica et Biophysica Acta, 1473(1), 67–95.

    CAS  PubMed  Google Scholar 

  10. Pinho, S. S., & Reis, C. A. (2015). Glycosylation in cancer: mechanisms and clinical implications. Nature Reviews. Cancer, 15(9), 540–555. https://doi.org/10.1038/nrc3982.

    Article  CAS  PubMed  Google Scholar 

  11. Barrera, M. J., Aguilera, S., Veerman, E., Quest, A. F., Diaz-Jimenez, D., Urzua, U., et al. (2015). Salivary mucins induce a Toll-like receptor 4-mediated pro-inflammatory response in human submandibular salivary cells: are mucins involved in Sjogren's syndrome? Rheumatology (Oxford), 54(8), 1518–1527. https://doi.org/10.1093/rheumatology/kev026.

    Article  CAS  Google Scholar 

  12. Hollingsworth, M. A., & Swanson, B. J. (2004). Mucins in cancer: protection and control of the cell surface. Nature Reviews. Cancer, 4(1), 45–60. https://doi.org/10.1038/nrc1251.

    Article  CAS  PubMed  Google Scholar 

  13. Agrawal, B., Krantz, M. J., Reddish, M. A., & Longenecker, B. M. (1998). Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nature Medicine, 4(1), 43–49.

    CAS  PubMed  Google Scholar 

  14. Van Seuningen, I., Pigny, P., Perrais, M., Porchet, N., & Aubert, J. P. (2001). Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer? Frontiers in Bioscience, 6, D1216–D1234.

    PubMed  Google Scholar 

  15. McAuley, J. L., Linden, S. K., Png, C. W., King, R. M., Pennington, H. L., Gendler, S. J., et al. (2007). MUC1 cell surface mucin is a critical element of the mucosal barrier to infection. The Journal of Clinical Investigation, 117(8), 2313–2324. https://doi.org/10.1172/jci26705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Linden, S. K., Florin, T. H., & McGuckin, M. A. (2008). Mucin dynamics in intestinal bacterial infection. PLoS One, 3(12), e3952. https://doi.org/10.1371/journal.pone.0003952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cornelissen, L. A., & Van Vliet, S. J. (2016). A bitter sweet symphony: immune responses to altered O-glycan epitopes in cancer. Biomolecules, 6(2). https://doi.org/10.3390/biom6020026.

  18. Chauhan, S. C., Kumar, D., & Jaggi, M. (2009). Mucins in ovarian cancer diagnosis and therapy. Journal of Ovarian Research, 2, 21. https://doi.org/10.1186/1757-2215-2-21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Komatsu, M., Yee, L., & Carraway, K. L. (1999). Overexpression of sialomucin complex, a rat homologue of MUC4, inhibits tumor killing by lymphokine-activated killer cells. Cancer Research, 59(9), 2229–2236.

    CAS  PubMed  Google Scholar 

  20. van de Wiel-van Kemenade, E., Ligtenberg, M. J., de Boer, A. J., Buijs, F., Vos, H. L., Melief, C. J., et al. (1993). Episialin (MUC1) inhibits cytotoxic lymphocyte-target cell interaction. Journal of Immunology, 151(2), 767–776.

    Google Scholar 

  21. Marcos-Silva, L., Ricardo, S., Chen, K., Blixt, O., Arigi, E., Pereira, D., et al. (2015). A novel monoclonal antibody to a defined peptide epitope in MUC16. Glycobiology, 25(11), 1172–1182. https://doi.org/10.1093/glycob/cwv056.

    Article  CAS  PubMed  Google Scholar 

  22. von Mensdorff-Pouilly, S., Verstraeten, A. A., Kenemans, P., Snijdewint, F. G., Kok, A., Van Kamp, G. J., et al. (2000). Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. Journal of Clinical Oncology, 18(3), 574–583. https://doi.org/10.1200/jco.2000.18.3.574.

    Article  Google Scholar 

  23. Blixt, O., Bueti, D., Burford, B., Allen, D., Julien, S., Hollingsworth, M., et al. (2011). Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis. Breast Cancer Research, 13(2), R25. https://doi.org/10.1186/bcr2841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Balachandran, V. P., Luksza, M., Zhao, J. N., Makarov, V., Moral, J. A., Remark, R., et al. (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature, 551(7681), 512–516. https://doi.org/10.1038/nature24462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lloyd, K. O., Burchell, J., Kudryashov, V., Yin, B. W., & Taylor-Papadimitriou, J. (1996). Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. Demonstration of simpler and fewer glycan chains in tumor cells. The Journal of Biological Chemistry, 271(52), 33325–33334.

    CAS  PubMed  Google Scholar 

  26. Croce, M. V., Isla-Larrain, M. T., Capafons, A., Price, M. R., & Segal-Eiras, A. (2001). Humoral immune response induced by the protein core of MUC1 mucin in pregnant and healthy women. Breast Cancer Research and Treatment, 69(1), 1–11.

    CAS  PubMed  Google Scholar 

  27. Cai, H., Palitzsch, B., Hartmann, S., Stergiou, N., Kunz, H., Schmitt, E., et al. (2015). Antibody induction directed against the tumor-associated MUC4 glycoprotein. Chembiochem, 16(6), 959–967. https://doi.org/10.1002/cbic.201402689.

    Article  CAS  PubMed  Google Scholar 

  28. Barnd, D. L., Lan, M. S., Metzgar, R. S., & Finn, O. J. (1989). Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proceedings of the National Academy of Sciences of the United States of America, 86(18), 7159–7163.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Karsten, U., Serttas, N., Paulsen, H., Danielczyk, A., & Goletz, S. (2004). Binding patterns of DTR-specific antibodies reveal a glycosylation-conditioned tumor-specific epitope of the epithelial mucin (MUC1). Glycobiology, 14(8), 681–692. https://doi.org/10.1093/glycob/cwh090.

    Article  CAS  PubMed  Google Scholar 

  30. Grinstead, J. S., Schuman, J. T., & Campbell, A. P. (2003). Epitope mapping of antigenic MUC1 peptides to breast cancer antibody fragment B27.29: a heteronuclear NMR study. Biochemistry, 42(48), 14293–14305. https://doi.org/10.1021/bi0301237.

    Article  CAS  PubMed  Google Scholar 

  31. Hanisch, F. G., Schwientek, T., Von Bergwelt-Baildon, M. S., Schultze, J. L., & Finn, O. (2003). O-linked glycans control glycoprotein processing by antigen-presenting cells: a biochemical approach to the molecular aspects of MUC1 processing by dendritic cells. European Journal of Immunology, 33(12), 3242–3254. https://doi.org/10.1002/eji.200324189.

    Article  CAS  PubMed  Google Scholar 

  32. Anandkumar, A., & Devaraj, H. (2013). Tumour immunomodulation: mucins in resistance to initiation and maturation of immune response against tumours. Scandinavian Journal of Immunology, 78(1), 1–7. https://doi.org/10.1111/sji.12019.

    Article  CAS  PubMed  Google Scholar 

  33. Hauselmann, I., & Borsig, L. (2014). Altered tumor-cell glycosylation promotes metastasis. Frontiers in Oncology, 4, 28. https://doi.org/10.3389/fonc.2014.00028.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cousin, J. M., & Cloninger, M. J. (2016). The role of galectin-1 in cancer progression, and synthetic multivalent systems for the study of galectin-1. International Journal of Molecular Sciences, 17(9). https://doi.org/10.3390/ijms17091566.

  35. Ogata, S., Maimonis, P. J., & Itzkowitz, S. H. (1992). Mucins bearing the cancer-associated sialosyl-Tn antigen mediate inhibition of natural killer cell cytotoxicity. Cancer Research, 52(17), 4741–4746.

    CAS  PubMed  Google Scholar 

  36. Rakoff-Nahoum, S., & Medzhitov, R. (2009). Toll-like receptors and cancer. Nature Reviews. Cancer, 9(1), 57–63. https://doi.org/10.1038/nrc2541.

    Article  CAS  PubMed  Google Scholar 

  37. Schmidt, C. (2006). Immune system’s Toll-like receptors have good opportunity for cancer treatment. Journal of the National Cancer Institute, 98(9), 574–575. https://doi.org/10.1093/jnci/djj198.

    Article  PubMed  Google Scholar 

  38. Madsen, C. B., Petersen, C., Lavrsen, K., Harndahl, M., Buus, S., Clausen, H., et al. (2012). Cancer associated aberrant protein O-glycosylation can modify antigen processing and immune response. PLoS One, 7(11), e50139. https://doi.org/10.1371/journal.pone.0050139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tarang, S., Kumar, S., & Batra, S. K. (2012). Mucins and toll-like receptors: kith and kin in infection and cancer. Cancer Letters, 321(2), 110–119. https://doi.org/10.1016/j.canlet.2012.01.040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Menon, B. B., Kaiser-Marko, C., Spurr-Michaud, S., Tisdale, A. S., & Gipson, I. K. (2015). Suppression of Toll-like receptor-mediated innate immune responses at the ocular surface by the membrane-associated mucins MUC1 and MUC16. Mucosal Immunology, 8(5), 1000–1008. https://doi.org/10.1038/mi.2014.127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Patankar, M. S., Jing, Y., Morrison, J. C., Belisle, J. A., Lattanzio, F. A., Deng, Y., et al. (2005). Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecologic Oncology, 99(3), 704–713. https://doi.org/10.1016/j.ygyno.2005.07.030.

    Article  CAS  PubMed  Google Scholar 

  42. Belisle, J. A., Gubbels, J. A., Raphael, C. A., Migneault, M., Rancourt, C., Connor, J. P., et al. (2007). Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology, 122(3), 418–429. https://doi.org/10.1111/j.1365-2567.2007.02660.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gubbels, J. A., Felder, M., Horibata, S., Belisle, J. A., Kapur, A., Holden, H., et al. (2010). MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Molecular Cancer, 9, 11. https://doi.org/10.1186/1476-4598-9-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Schreiber, J., Stahn, R., Schenk, J. A., Karsten, U., & Pecher, G. (2000). Binding of tumor antigen mucin (MUC1) derived peptides to the heat shock protein DnaK. Anticancer Research, 20(5a), 3093–3098.

    CAS  PubMed  Google Scholar 

  45. Hiltbold, E. M., Vlad, A. M., Ciborowski, P., Watkins, S. C., & Finn, O. J. (2000). The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells. Journal of Immunology, 165(7), 3730–3741.

    CAS  Google Scholar 

  46. Apostolopoulos, V., Yuriev, E., Ramsland, P. A., Halton, J., Osinski, C., Li, W., et al. (2003). A glycopeptide in complex with MHC class I uses the GalNAc residue as an anchor. Proceedings of the National Academy of Sciences of the United States of America, 100(25), 15029–15034. https://doi.org/10.1073/pnas.2432220100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ninkovic, T., Kinarsky, L., Engelmann, K., Pisarev, V., Sherman, S., Finn, O. J., et al. (2009). Identification of O-glycosylated decapeptides within the MUC1 repeat domain as potential MHC class I (A2) binding epitopes. Molecular Immunology, 47(1), 131–140. https://doi.org/10.1016/j.molimm.2008.09.032.

    Article  CAS  PubMed  Google Scholar 

  48. Shan, M., Gentile, M., Yeiser, J. R., Walland, A. C., Bornstein, V. U., Chen, K., et al. (2013). Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science, 342(6157), 447–453. https://doi.org/10.1126/science.1237910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Monti, P., Leone, B. E., Zerbi, A., Balzano, G., Cainarca, S., Sordi, V., et al. (2004). Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10highIL-12low regulatory dendritic cell. Journal of Immunology, 172(12), 7341–7349.

    CAS  Google Scholar 

  50. Ohta, M., Ishida, A., Toda, M., Akita, K., Inoue, M., Yamashita, K., et al. (2010). Immunomodulation of monocyte-derived dendritic cells through ligation of tumor-produced mucins to Siglec-9. Biochemical and Biophysical Research Communications, 402(4), 663–669. https://doi.org/10.1016/j.bbrc.2010.10.079.

    Article  CAS  PubMed  Google Scholar 

  51. Rughetti, A., Pellicciotta, I., Biffoni, M., Backstrom, M., Link, T., Bennet, E. P., et al. (2005). Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells. Journal of Immunology, 174(12), 7764–7772.

    CAS  Google Scholar 

  52. Williams, M. A., Bauer, S., Lu, W., Guo, J., Walter, S., Bushnell, T. P., et al. (2010). Deletion of the mucin-like molecule muc1 enhances dendritic cell activation in response to toll-like receptor ligands. Journal of Innate Immunity, 2(2), 123–143. https://doi.org/10.1159/000254790.

    Article  CAS  PubMed  Google Scholar 

  53. Wykes, M., MacDonald, K. P., Tran, M., Quin, R. J., Xing, P. X., Gendler, S. J., et al. (2002). MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells. Journal of Leukocyte Biology, 72(4), 692–701.

    CAS  PubMed  Google Scholar 

  54. Zhu, Y., Zhang, J. J., Liang, W. B., Zhu, R., Wang, B., Miao, Y., et al. (2014). Pancreatic cancer counterattack: MUC4 mediates Fas-independent apoptosis of antigen-specific cytotoxic T lymphocyte. Oncology Reports, 31(4), 1768–1776. https://doi.org/10.3892/or.2014.3016.

    Article  CAS  PubMed  Google Scholar 

  55. Karanikas, V., Hwang, L. A., Pearson, J., Ong, C. S., Apostolopoulos, V., Vaughan, H., et al. (1997). Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. The Journal of Clinical Investigation, 100(11), 2783–2792. https://doi.org/10.1172/jci119825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ioannides, C. G., Fisk, B., Jerome, K. R., Irimura, T., Wharton, J. T., & Finn, O. J. (1993). Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. Journal of Immunology, 151(7), 3693–3703.

    CAS  Google Scholar 

  57. Barratt-Boyes, S. M., Vlad, A., & Finn, O. J. (1999). Immunization of chimpanzees with tumor antigen MUC1 mucin tandem repeat peptide elicits both helper and cytotoxic T-cell responses. Clinical Cancer Research, 5(7), 1918–1924.

    CAS  PubMed  Google Scholar 

  58. Graves, C. R., Robertson, J. F., Murray, A., Price, M. R., & Chapman, C. J. (2005). Malignancy-induced autoimmunity to MUC1: initial antibody characterization. The Journal of Peptide Research, 66(6), 357–363. https://doi.org/10.1111/j.1399-3011.2005.00297.x.

    Article  CAS  PubMed  Google Scholar 

  59. von Mensdorff-Pouilly, S., Petrakou, E., Kenemans, P., van Uffelen, K., Verstraeten, A. A., Snijdewint, F. G., et al. (2000). Reactivity of natural and induced human antibodies to MUC1 mucin with MUC1 peptides and n-acetylgalactosamine (GalNAc) peptides. International Journal of Cancer, 86(5), 702–712.

    Google Scholar 

  60. Coltart, D. M., Royyuru, A. K., Williams, L. J., Glunz, P. W., Sames, D., Kuduk, S. D., et al. (2002). Principles of mucin architecture: structural studies on synthetic glycopeptides bearing clustered mono-, di-, tri-, and hexasaccharide glycodomains. Journal of the American Chemical Society, 124(33), 9833–9844.

    CAS  PubMed  Google Scholar 

  61. Dziadek, S., Griesinger, C., Kunz, H., & Reinscheid, U. M. (2006). Synthesis and structural model of an alpha(2,6)-sialyl-t glycosylated MUC1 eicosapeptide under physiological conditions. Chemistry, 12(19), 4981–4993. https://doi.org/10.1002/chem.200600144.

    Article  CAS  PubMed  Google Scholar 

  62. Fremd, C., Stefanovic, S., Beckhove, P., Pritsch, M., Lim, H., Wallwiener, M., et al. (2016). Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients. Oncoimmunology, 5(1), e1057387. https://doi.org/10.1080/2162402x.2015.1057387.

    Article  PubMed  Google Scholar 

  63. McEver, R. P. (2015). Selectins: Initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovascular Research, 107(3), 331–339. https://doi.org/10.1093/cvr/cvv154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Baldus, S. E., Monig, S. P., Hanisch, F. G., Zirbes, T. K., Flucke, U., Oelert, S., et al. (2002). Comparative evaluation of the prognostic value of MUC1, MUC2, sialyl-Lewis(a) and sialyl-Lewis(x) antigens in colorectal adenocarcinoma. Histopathology, 40(5), 440–449.

    CAS  PubMed  Google Scholar 

  65. Chen, S. H., Dallas, M. R., Balzer, E. M., & Konstantopoulos, K. (2012). Mucin 16 is a functional selectin ligand on pancreatic cancer cells. The FASEB Journal, 26(3), 1349–1359. https://doi.org/10.1096/fj.11-195669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Park, J., Wysocki, R. W., Amoozgar, Z., Maiorino, L., Fein, M. R., Jorns, J., et al. (2016). Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Science Translational Medicine, 8(361), 361ra138. https://doi.org/10.1126/scitranslmed.aag1711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rowson-Hodel, A. R., Wald, J. H., Hatakeyama, J., O'Neal, W. K., Stonebraker, J. R., VanderVorst, K., et al. (2018). Membrane mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene, 37(2), 197–207. https://doi.org/10.1038/onc.2017.327.

    Article  CAS  PubMed  Google Scholar 

  68. Hsu, H. P., Lai, M. D., Lee, J. C., Yen, M. C., Weng, T. Y., Chen, W. C., et al. (2017). Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. Scientific Reports, 7(1), 5823. https://doi.org/10.1038/s41598-017-04952-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hoshi, H., Sawada, T., Uchida, M., Iijima, H., Kimura, K., Hirakawa, K., et al. (2013). MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways. International Journal of Oncology, 42(3), 887–893. https://doi.org/10.3892/ijo.2013.1760.

    Article  CAS  PubMed  Google Scholar 

  70. Theriault, C., Pinard, M., Comamala, M., Migneault, M., Beaudin, J., Matte, I., et al. (2011). MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecologic Oncology, 121(3), 434–443. https://doi.org/10.1016/j.ygyno.2011.02.020.

    Article  CAS  PubMed  Google Scholar 

  71. Mori, Y., Akita, K., Tanida, S., Ishida, A., Toda, M., Inoue, M., et al. (2014). MUC1 protein induces urokinase-type plasminogen activator (uPA) by forming a complex with NF-kappaB p65 transcription factor and binding to the uPA promoter, leading to enhanced invasiveness of cancer cells. The Journal of Biological Chemistry, 289(51), 35193–35204. https://doi.org/10.1074/jbc.M114.586461.

  72. Wittel, U. A., Goel, A., Varshney, G. C., & Batra, S. K. (2001). Mucin antibodies—new tools in diagnosis and therapy of cancer. Frontiers in Bioscience, 6, D1296–D1310.

    CAS  PubMed  Google Scholar 

  73. Hughes, O. D., Perkins, A. C., Frier, M., Wastie, M. L., Denton, G., Price, M. R., et al. (2001). Imaging for staging bladder cancer: a clinical study of intravenous 111indium-labelled anti-MUC1 mucin monoclonal antibody C595. BJU International, 87(1), 39–46.

    CAS  PubMed  Google Scholar 

  74. Hughes, O. D., Bishop, M. C., Perkins, A. C., Frier, M., Price, M. R., Denton, G., et al. (1997). Preclinical evaluation of copper-67 labelled anti-MUC1 mucin antibody C595 for therapeutic use in bladder cancer. European Journal of Nuclear Medicine, 24(4), 439–443.

    CAS  PubMed  Google Scholar 

  75. Hughes, O. D., Bishop, M. C., Perkins, A. C., Wastie, M. L., Denton, G., Price, M. R., et al. (2000). Targeting superficial bladder cancer by the intravesical administration of copper-67-labeled anti-MUC1 mucin monoclonal antibody C595. Journal of Clinical Oncology, 18(2), 363–370. https://doi.org/10.1200/jco.2000.18.2.363.

    Article  CAS  PubMed  Google Scholar 

  76. Noujaim, A. A., Schultes, B. C., Baum, R. P., & Madiyalakan, R. (2001). Induction of CA125-specific B and T cell responses in patients injected with MAb-B43.13—evidence for antibody-mediated antigen-processing and presentation of CA125 in vivo. Cancer Biotherapy & Radiopharmaceuticals, 16(3), 187–203. https://doi.org/10.1089/10849780152389384.

    Article  CAS  Google Scholar 

  77. Ehlen, T. G., Hoskins, P. J., Miller, D., Whiteside, T. L., Nicodemus, C. F., Schultes, B. C., et al. (2005). A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer. International Journal of Gynecological Cancer, 15(6), 1023–1034. https://doi.org/10.1111/j.1525-1438.2005.00483.x.

    Article  CAS  PubMed  Google Scholar 

  78. Berek, J., Taylor, P., McGuire, W., Smith, L. M., Schultes, B., & Nicodemus, C. F. (2009). Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol, 27(3), 418-425, https://doi.org/10.1200/jco.2008.17.8400.

  79. Singh, A. P., Senapati, S., Ponnusamy, M. P., Jain, M., Lele, S. M., Davis, J. S., et al. (2008). Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer. The Lancet Oncology, 9(11), 1076–1085. https://doi.org/10.1016/s1470-2045(08)70277-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Burchell, J., Gendler, S., Taylor-Papadimitriou, J., Girling, A., Lewis, A., Millis, R., et al. (1987). Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Cancer Research, 47(20), 5476–5482.

    CAS  PubMed  Google Scholar 

  81. Verhoeyen, M. E., Saunders, J. A., Price, M. R., Marugg, J. D., Briggs, S., Broderick, E. L., et al. (1993). Construction of a reshaped HMFG1 antibody and comparison of its fine specificity with that of the parent mouse antibody. Immunology, 78(3), 364–370.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ibrahim, N. K., Yariz, K. O., Bondarenko, I., Manikhas, A., Semiglazov, V., Alyasova, A., et al. (2011). Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer. Clinical Cancer Research, 17(21), 6822–6830. https://doi.org/10.1158/1078-0432.Ccr-11-1151.

    Article  CAS  PubMed  Google Scholar 

  83. Song, H., & Sgouros, G. (2011). Radioimmunotherapy of solid tumors: searching for the right target. Current Drug Delivery, 8(1), 26–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Dian, D., Lenhard, M., Mayr, D., Heublein, S., Karsten, U., Goletz, S., et al. (2013). Staining of MUC1 in ovarian cancer tissues with PankoMab-GEX detecting the tumour-associated epitope, TA-MUC1, as compared to antibodies HMFG-1 and 115D8. Histology and Histopathology, 28(2), 239–244. https://doi.org/10.14670/hh-28.239.

    Article  PubMed  Google Scholar 

  85. Danielczyk, A., Stahn, R., Faulstich, D., Loffler, A., Marten, A., Karsten, U., et al. (2006). PankoMab: a potent new generation anti-tumour MUC1 antibody. Cancer Immunology, Immunotherapy, 55(11), 1337–1347. https://doi.org/10.1007/s00262-006-0135-9.

    Article  CAS  PubMed  Google Scholar 

  86. Fiedler, W., DeDosso, S., Cresta, S., Weidmann, J., Tessari, A., Salzberg, M., et al. (2016). A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. European Journal of Cancer, 63, 55–63. https://doi.org/10.1016/j.ejca.2016.05.003.

    Article  CAS  PubMed  Google Scholar 

  87. Fan, X. N., Karsten, U., Goletz, S., & Cao, Y. (2010). Reactivity of a humanized antibody (hPankoMab) towards a tumor-related MUC1 epitope (TA-MUC1) with various human carcinomas. Pathology, Research and Practice, 206(8), 585–589. https://doi.org/10.1016/j.prp.2010.03.006.

    Article  CAS  PubMed  Google Scholar 

  88. Felder, M., Kapur, A., Gonzalez-Bosquet, J., Horibata, S., Heintz, J., Albrecht, R., et al. (2014). MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Molecular Cancer, 13, 129. https://doi.org/10.1186/1476-4598-13-129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Patel, S. P., Bristol, A., Saric, O., Wang, X. P., Dubeykovskiy, A., Arlen, P. M., et al. (2013). Anti-tumor activity of a novel monoclonal antibody, NPC-1C, optimized for recognition of tumor antigen MUC5AC variant in preclinical models. Cancer Immunology, Immunotherapy, 62(6), 1011–1019. https://doi.org/10.1007/s00262-013-1420-z.

    Article  CAS  PubMed  Google Scholar 

  90. Larson, S. M., Carrasquillo, J. A., Cheung, N. K., & Press, O. W. (2015). Radioimmunotherapy of human tumours. Nature Reviews. Cancer, 15(6), 347–360. https://doi.org/10.1038/nrc3925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kufe, D. W. (2009). Mucins in cancer: function, prognosis and therapy. Nature Reviews. Cancer, 9(12), 874–885. https://doi.org/10.1038/nrc2761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Price, M. R., Sekowski, M., & Tendler, S. J. (1991). Purification of anti-epithelial mucin monoclonal antibodies by epitope affinity chromatography. Journal of Immunological Methods, 139(1), 83–90.

    CAS  PubMed  Google Scholar 

  93. Buckman, R., De Angelis, C., Shaw, P., Covens, A., Osborne, R., Kerr, I., et al. (1992). Intraperitoneal therapy of malignant ascites associated with carcinoma of ovary and breast using radioiodinated monoclonal antibody 2G3. Gynecologic Oncology, 47(1), 102–109.

    CAS  PubMed  Google Scholar 

  94. Peterson, J. A., & Ceriani, R. L. (1994). Breast mucin and associated antigens in diagnosis and therapy. Advances in Experimental Medicine and Biology, 353, 1–8.

    CAS  PubMed  Google Scholar 

  95. Murray, A., Simms, M. S., Scholfield, D. P., Vincent, R. M., Denton, G., Bishop, M. C., et al. (2001). Production and characterization of 188Re-C595 antibody for radioimmunotherapy of transitional cell bladder cancer. Journal of Nuclear Medicine, 42(5), 726–732.

    CAS  PubMed  Google Scholar 

  96. Supiot, S., Faivre-Chauvet, A., Couturier, O., Heymann, M. F., Robillard, N., Kraeber-Bodere, F., et al. (2002). Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma. Cancer, 94(4 Suppl), 1202–1209.

    CAS  PubMed  Google Scholar 

  97. Berger, M. A., Masters, G. R., Singleton, J., Scully, M. S., Grimm, L. G., Soltis, D. A., et al. (2005). Pharmacokinetics, biodistribution, and radioimmunotherapy with monoclonal antibody 776.1 in a murine model of human ovarian cancer. Cancer Biotherapy & Radiopharmaceuticals, 20(6), 589–602. https://doi.org/10.1089/cbr.2005.20.589.

    Article  CAS  Google Scholar 

  98. Garkavij, M., Samarzija, M., Ewers, S. B., Jakopovic, M., Tezak, S., & Tennvall, J. (2005). Concurrent radiotherapy and tumor targeting with 111In-HMFG1-F(ab')2 in patients with MUC1-positive non-small cell lung cancer. Anticancer Research, 25(6c), 4663–4671.

    CAS  PubMed  Google Scholar 

  99. Qu, C. F., Songl, Y. J., Rizvi, S. M., Li, Y., Smith, R., Perkins, A. C., et al. (2005). In vivo and in vitro inhibition of pancreatic cancer growth by targeted alpha therapy using 213Bi-CHX.A″-C595. Cancer Biology & Therapy, 4(8), 848–853.

    CAS  Google Scholar 

  100. Song, E. Y., Qu, C. F., Rizvi, S. M., Raja, C., Beretov, J., Morgenstern, A., et al. (2008). Bismuth-213 radioimmunotherapy with C595 anti-MUC1 monoclonal antibody in an ovarian cancer ascites model. Cancer Biology & Therapy, 7(1), 76–80.

    CAS  Google Scholar 

  101. Salouti, M., Babaei, M. H., Rajabi, H., & Rasaee, M. (2011). Preparation and biological evaluation of (177)Lu conjugated PR81 for radioimmunotherapy of breast cancer. Nuclear Medicine and Biology, 38(6), 849–855. https://doi.org/10.1016/j.nucmedbio.2011.02.009.

    Article  CAS  PubMed  Google Scholar 

  102. Cardillo, T. M., Ying, Z., & Gold, D. V. (2001). Therapeutic advantage of (90)yttrium- versus (131)iodine-labeled PAM4 antibody in experimental pancreatic cancer. Clinical Cancer Research, 7(10), 3186–3192.

    CAS  PubMed  Google Scholar 

  103. Han, S., Jin, G., Wang, L., Li, M., He, C., Guo, X., et al. (2014). The role of PAM4 in the management of pancreatic cancer: diagnosis, radioimmunodetection, and radioimmunotherapy. Journal of Immunology Research, 2014, 268479. https://doi.org/10.1155/2014/268479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Maraveyas, A., Snook, D., Hird, V., Kosmas, C., Meares, C. F., Lambert, H. E., et al. (1994). Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer, 73(3 Suppl), 1067–1075.

    CAS  PubMed  Google Scholar 

  105. Maraveyas, A., Stafford, N., Rowlinson-Busza, G., Stewart, J. S., & Epenetos, A. A. (1995). Pharmacokinetics, biodistribution, and dosimetry of specific and control radiolabeled monoclonal antibodies in patients with primary head and neck squamous cell carcinoma. Cancer Research, 55(5), 1060–1069.

    CAS  PubMed  Google Scholar 

  106. Gulec, S. A., Cohen, S. J., Pennington, K. L., Zuckier, L. S., Hauke, R. J., Horne, H., et al. (2011). Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial. Clinical Cancer Research, 17(12), 4091–4100. https://doi.org/10.1158/1078-0432.CCR-10-2579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Picozzi, V. J., Ramanathan, R. K., Lowery, M. A., Ocean, A. J., Mitchel, E. P., O'Neil, B. H., et al. (2015). (90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: a phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies. European Journal of Cancer, 51(14), 1857–1864. https://doi.org/10.1016/j.ejca.2015.06.119.

    Article  CAS  PubMed  Google Scholar 

  108. Gold, D. V., Newsome, G., Liu, D., & Goldenberg, D. M. (2013). Mapping PAM4 (clivatuzumab), a monoclonal antibody in clinical trials for early detection and therapy of pancreatic ductal adenocarcinoma, to MUC5AC mucin. Molecular Cancer, 12(1), 143. https://doi.org/10.1186/1476-4598-12-143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Peterson, J. A., Couto, J. R., Taylor, M. R., & Ceriani, R. L. (1995). Selection of tumor-specific epitopes on target antigens for radioimmunotherapy of breast cancer. Cancer Research, 55(23 Suppl), 5847s–5851s.

    CAS  PubMed  Google Scholar 

  110. Mariani, G., Molea, N., Bacciardi, D., Boggi, U., Fornaciari, G., Campani, D., et al. (1995). Initial tumor targeting, biodistribution, and pharmacokinetic evaluation of the monoclonal antibody PAM4 in patients with pancreatic cancer. Cancer Research, 55(23 Suppl), 5911s–5915s.

    CAS  PubMed  Google Scholar 

  111. Gold, D. V., Cardillo, T., Goldenberg, D. M., & Sharkey, R. M. (2001). Localization of pancreatic cancer with radiolabeled monoclonal antibody PAM4. Critical Reviews in Oncology/Hematology, 39(1–2), 147–154.

    CAS  PubMed  Google Scholar 

  112. Cardillo, T. M., Blumenthal, R., Ying, Z., & Gold, D. V. (2002). Combined gemcitabine and radioimmunotherapy for the treatment of pancreatic cancer. International Journal of Cancer, 97(3), 386–392.

    CAS  PubMed  Google Scholar 

  113. Gold, D. V., Schutsky, K., Modrak, D., & Cardillo, T. M. (2003). Low-dose radioimmunotherapy ((90)Y-PAM4) combined with gemcitabine for the treatment of experimental pancreatic cancer. Clinical Cancer Research, 9(10 Pt 2), 3929s–3937s.

    CAS  PubMed  Google Scholar 

  114. Gold, D. V., Modrak, D. E., Schutsky, K., & Cardillo, T. M. (2004). Combined 90Yttrium-DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft. International Journal of Cancer, 109(4), 618–626. https://doi.org/10.1002/ijc.20004.

    Article  CAS  PubMed  Google Scholar 

  115. Greiner, J. W., Ullmann, C. D., Nieroda, C., Qi, C. F., Eggensperger, D., Shimada, S., et al. (1993). Improved radioimmunotherapeutic efficacy of an anticarcinoma monoclonal antibody (131I-CC49) when given in combination with gamma-interferon. Cancer Research, 53(3), 600–608.

    CAS  PubMed  Google Scholar 

  116. Molthoff, C. F., Pinedo, H. M., Schluper, H. M., Rutgers, D. H., & Boven, E. (1992). Comparison of 131I-labelled anti-episialin 139H2 with cisplatin, cyclophosphamide or external-beam radiation for anti-tumor efficacy in human ovarian cancer xenografts. International Journal of Cancer, 51(1), 108–115.

    CAS  PubMed  Google Scholar 

  117. Jain, M., Chauhan, S. C., Singh, A. P., Venkatraman, G., Colcher, D., & Batra, S. K. (2005). Penetratin improves tumor retention of single-chain antibodies: a novel step toward optimization of radioimmunotherapy of solid tumors. Cancer Research, 65(17), 7840–7846. https://doi.org/10.1158/0008-5472.Can-05-0662.

    Article  CAS  PubMed  Google Scholar 

  118. Wittel, U. A., Jain, M., Goel, A., Baranowska-Kortylewicz, J., Kurizaki, T., Chauhan, S. C., et al. (2005). Engineering and characterization of a divalent single-chain Fv angiotensin II fusion construct of the monoclonal antibody CC49. Biochemical and Biophysical Research Communications, 329(1), 168–176. https://doi.org/10.1016/j.bbrc.2005.01.101.

    Article  CAS  PubMed  Google Scholar 

  119. Jain, M., Venkatraman, G., & Batra, S. K. (2007). Cell-penetrating peptides and antibodies: a new direction for optimizing radioimmunotherapy. European Journal of Nuclear Medicine and Molecular Imaging, 34(7), 973–977. https://doi.org/10.1007/s00259-007-0395-4.

    Article  PubMed  Google Scholar 

  120. Moniaux, N., Varshney, G. C., Chauhan, S. C., Copin, M. C., Jain, M., Wittel, U. A., et al. (2004). Generation and characterization of anti-MUC4 monoclonal antibodies reactive with normal and cancer cells in humans. The Journal of Histochemistry and Cytochemistry, 52(2), 253–261. https://doi.org/10.1177/002215540405200213.

    Article  CAS  PubMed  Google Scholar 

  121. Jain, M., Venkatraman, G., Moniaux, N., Kaur, S., Kumar, S., Chakraborty, S., et al. (2011). Monoclonal antibodies recognizing the non-tandem repeat regions of the human mucin MUC4 in pancreatic cancer. PLoS One, 6(8), e23344. https://doi.org/10.1371/journal.pone.0023344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gautam, S. K., Kumar, S., Cannon, A., Hall, B., Bhatia, R., Nasser, M. W., et al. (2017). MUC4 mucin—a therapeutic target for pancreatic ductal adenocarcinoma. Expert Opinion on Therapeutic Targets, 21(7), 657–669. https://doi.org/10.1080/14728222.2017.1323880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Batra, S. K., Jain, M., Wittel, U. A., Chauhan, S. C., & Colcher, D. (2002). Pharmacokinetics and biodistribution of genetically engineered antibodies. Current Opinion in Biotechnology, 13(6), 603–608.

    CAS  PubMed  Google Scholar 

  124. Jain, M., & Batra, S. K. (2003). Genetically engineered antibody fragments and PET imaging: a new era of radioimmunodiagnosis. Journal of Nuclear Medicine, 44(12), 1970–1972.

    PubMed  Google Scholar 

  125. Jain, M., Kamal, N., & Batra, S. K. (2007). Engineering antibodies for clinical applications. Trends in Biotechnology, 25(7), 307–316. https://doi.org/10.1016/j.tibtech.2007.05.001.

    Article  CAS  PubMed  Google Scholar 

  126. Goydos, J. S., Elder, E., Whiteside, T. L., Finn, O. J., & Lotze, M. T. (1996). A phase I trial of a synthetic mucin peptide vaccine. Induction of specific immune reactivity in patients with adenocarcinoma. The Journal of Surgical Research, 63(1), 298–304. https://doi.org/10.1006/jsre.1996.0264.

    Article  CAS  PubMed  Google Scholar 

  127. Gilewski, T., Adluri, S., Ragupathi, G., Zhang, S., Yao, T. J., Panageas, K., et al. (2000). Vaccination of high-risk breast cancer patients with mucin-1 (MUC1) keyhole limpet hemocyanin conjugate plus QS-21. Clinical Cancer Research, 6(5), 1693–1701.

    CAS  PubMed  Google Scholar 

  128. Musselli, C., Ragupathi, G., Gilewski, T., Panageas, K. S., Spinat, Y., & Livingston, P. O. (2002). Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1. International Journal of Cancer, 97(5), 660–667.

    CAS  PubMed  Google Scholar 

  129. Sharma, S., Srivastava, M. K., Harris-White, M., Lee, J. M., & Dubinett, S. (2011). MUC1 peptide vaccine mediated antitumor activity in non-small cell lung cancer. Expert Opinion on Biological Therapy, 11(8), 987–990. https://doi.org/10.1517/14712598.2011.598146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sangha, R., & Butts, C. (2007). L-BLP25: a peptide vaccine strategy in non small cell lung cancer. Clinical Cancer Research, 13(15 Pt 2), s4652–s4654. https://doi.org/10.1158/1078-0432.Ccr-07-0213.

    Article  PubMed  Google Scholar 

  131. Xia, W., Wang, J., Xu, Y., Jiang, F., & Xu, L. (2014). L-BLP25 as a peptide vaccine therapy in non-small cell lung cancer: a review. Journal of Thoracic Disease, 6(10), 1513–1520. https://doi.org/10.3978/j.issn.2072-1439.2014.08.17.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Oudard, S., Rixe, O., Beuselinck, B., Linassier, C., Banu, E., Machiels, J. P., et al. (2011). A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings. Cancer Immunology, Immunotherapy, 60(2), 261–271. https://doi.org/10.1007/s00262-010-0935-9.

    Article  CAS  PubMed  Google Scholar 

  133. Ramlau, R., Quoix, E., Rolski, J., Pless, M., Lena, H., Levy, E., et al. (2008). A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer. Journal of Thoracic Oncology, 3(7), 735–744. https://doi.org/10.1097/JTO.0b013e31817c6b4f.

    Article  PubMed  Google Scholar 

  134. Dreicer, R., Stadler, W. M., Ahmann, F. R., Whiteside, T., Bizouarne, N., Acres, B., et al. (2009). MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure. Investigational New Drugs, 27(4), 379–386. https://doi.org/10.1007/s10637-008-9187-3.

    Article  CAS  PubMed  Google Scholar 

  135. Quoix, E., Ramlau, R., Westeel, V., Papai, Z., Madroszyk, A., Riviere, A., et al. (2011). Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. The Lancet Oncology, 12(12), 1125–1133. https://doi.org/10.1016/s1470-2045(11)70259-5.

    Article  CAS  PubMed  Google Scholar 

  136. Quoix, E., Lena, H., Losonczy, G., Forget, F., Chouaid, C., Papai, Z., et al. (2016). TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. The Lancet Oncology, 17(2), 212–223. https://doi.org/10.1016/s1470-2045(15)00483-0.

    Article  CAS  PubMed  Google Scholar 

  137. Dziadek, S., Kowalczyk, D., & Kunz, H. (2005). Synthetic vaccines consisting of tumor-associated MUC1 glycopeptide antigens and bovine serum albumin. Angewandte Chemie (International Ed. in English), 44(46), 7624–7630. https://doi.org/10.1002/anie.200501593.

    Article  CAS  Google Scholar 

  138. Ingale, S., Wolfert, M. A., Gaekwad, J., Buskas, T., & Boons, G. J. (2007). Robust immune responses elicited by a fully synthetic three-component vaccine. Nature Chemical Biology, 3(10), 663–667. https://doi.org/10.1038/nchembio.2007.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lakshminarayanan, V., Thompson, P., Wolfert, M. A., Buskas, T., Bradley, J. M., Pathangey, L. B., et al. (2012). Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proceedings of the National Academy of Sciences of the United States of America, 109(1), 261–266. https://doi.org/10.1073/pnas.1115166109.

    Article  PubMed  Google Scholar 

  140. Wu, J., Wei, J., Meng, K., Chen, J., Gao, W., Zhang, J., et al. (2009). Identification of an HLA-A*0201-restrictive CTL epitope from MUC4 for applicable vaccine therapy. Immunopharmacology and Immunotoxicology, 31(3), 468–476. https://doi.org/10.1080/08923970902795203.

    Article  CAS  PubMed  Google Scholar 

  141. Dobrzanski, M. J., Rewers-Felkins, K. A., Samad, K. A., Quinlin, I. S., Phillips, C. A., Robinson, W., et al. (2012). Immunotherapy with IL-10- and IFN-gamma-producing CD4 effector cells modulate “natural” and “inducible” CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer. Cancer Immunology, Immunotherapy, 61(6), 839–854. https://doi.org/10.1007/s00262-011-1128-x.

    Article  CAS  PubMed  Google Scholar 

  142. Lepisto, A. J., Moser, A. J., Zeh, H., Lee, K., Bartlett, D., McKolanis, J. R., et al. (2008). A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Therapy, 6(B), 955–964.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Pecher, G., Haring, A., Kaiser, L., & Thiel, E. (2002). Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunology, Immunotherapy, 51(11–12), 669–673. https://doi.org/10.1007/s00262-002-0317-z.

    Article  CAS  PubMed  Google Scholar 

  144. Kondo, H., Hazama, S., Kawaoka, T., Yoshino, S., Yoshida, S., Tokuno, K., et al. (2008). Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Research, 28(1b), 379–387.

    CAS  PubMed  Google Scholar 

  145. Posey, A. D., Jr., Schwab, R. D., Boesteanu, A. C., Steentoft, C., Mandel, U., Engels, B., et al. (2016). Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity, 44(6), 1444–1454. https://doi.org/10.1016/j.immuni.2016.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Hege, K. M., Bergsland, E. K., Fisher, G. A., Nemunaitis, J. J., Warren, R. S., McArthur, J. G., et al. (2017). Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. Journal for ImmunoTherapy of Cancer, 5, 22. https://doi.org/10.1186/s40425-017-0222-9.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Panchamoorthy, G., Jin, C., Raina, D., Bharti, A., Yamamoto, M., Adeebge, D., et al. (2018). Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.99880.

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Grant support

This work was supported by funding from the National Institutes of Health (PO1 CA 217798, P50 CA127297, UO1 CA210240, UO1 CA200466, UO 1 CA213862, R21 CA223429, F30 CA225117, R01 CA183459, RO1 CA 195586, RO1 CA206444, R21 AA 026428, and RO1 CA228524).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA

    Rakesh Bhatia, Shailendra K. Gautam, Andrew Cannon, Christopher Thompson, Abhijit Aithal, Kasturi Banerjee, Maneesh Jain, Sushil Kumar & Surinder K. Batra

  2. Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA

    Bradley R. Hall

  3. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Maneesh Jain & Surinder K. Batra

  4. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    Joyce C. Solheim & Surinder K. Batra

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  1. Rakesh Bhatia
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Correspondence to Surinder K. Batra.

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SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors have no potential conflicts of interest.

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Bhatia, R., Gautam, S.K., Cannon, A. et al. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev 38, 223–236 (2019). https://doi.org/10.1007/s10555-018-09775-0

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