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Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

A New Approach for Cancer Immunotherapy Based on the Cancer Stem Cell Antigens Properties

Author(s): Shirin Mahmoodi, Navid Nezafat*, Manica Negahdaripour and Younes Ghasemi*

Volume 19, Issue 1, 2019

Page: [2 - 11] Pages: 10

DOI: 10.2174/1566524019666190204114721

Price: $65


Background: Cancer stem cells (CSCs) are a rare population of tumor cells, which play an important role in tumor initiation, progression, and maintenance. The concept that cancer cells arise from stem cells was presented about 150 years ago. Recently, this hypothesis was renewed considering the heterogeneity of tumor cells. CSCs are resistant to chemo- and radio-therapy. Therefore, targeting CSCs could be a novel and effective strategy to struggle with tumor cells.

Objective: In this mini-review, we highlight that different immunotherapeutic approaches can be used to target cancer cells and eradicate different tumor cells. The most important targets are specific markers recognized on the CSC surface as CSC antigens such as CD44, CD133, Aldehyde Dehydrogenase (ALDH), and SOX family members. This article emphasizes recent advances in CSCs in cancer therapy.

Results: Our results present that CSC antigens play an important role in tumor initiation, especially in the cells that are resistant to chemo- and radiotherapy agents. Therefore, they are ideal targets for cancer immunotherapy, for instance, in developing different types of cancer vaccines or antibodies against tumor cells.

Conclusion: The current studies related to cancer immunotherapy through targeting the CSC antigens based on their properties are briefly summarized. Altogether, CSC antigens can be efficiently targeted to treat cancer patients.

Keywords: Cancer stem cell antigen, cancer immunotherapy, heterogeneity, target, tumor cells, stem cells.

Badve S, Nakshatri H. Breast-cancer stem cells beyond semantics. Lancet Oncol 2012; 13(1): 43-8.
Akbarzadeh A, Rahmati M, Taheri ZM, et al. Inhibition of hTERT Gene Expression by Silibin in-Loaded PLGA-PEG-Fe 3O4 in T47D Breast Cancer Cell Line Bioimpact 2013; 3(2): 67-74.
Rahmati-Yamchi M, Zarghami N, Rahbani M, Montazeri A. Plasma leptin, hTERT gene expression, and anthropometric measures in obese and non-obese women with breast cancer. Basic and clinical research 2011; 5: 27-5.
Neuzil J, Stantic M, Zobalova R, et al. Tumour-initiating cells vs. cancer ‘stem’cells and CD133: what’s in the name? Biochem Biophys Res Commun 2007; 355(4): 855-9.
Arens R, van Hall T, van der Burg SH, Ossendorp F, Melief CJ. editors. Prospects of combinatorial synthetic peptide vaccine-based immunotherapy against cancer. Semin Immunopathol 2013; 25: 182-90.
Engelmann K, Shen H, Finn OJ. MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res 2008; 68(7): 2419-26.
Kwiatkowska-Borowczyk EP, Gabka-Buszek A, Jankowski J, Mackiewicz A. Immunotargeting of cancer stem cells. Contemp Oncol (Pozn) 2015; 19(1): 52-9.
Constantinou A, Epenetos A, Hreczuk-Hirst D, et al. Site-specific polysialylation of an antitumor single-chain Fv fragment. Bioconjug Chem 2009; 20(5): 924-31.
Jordan CT, Guzman ML, Noble M. Cancer stem cells. New England Journal of Medicine 2006; 355(12): 1253-61.
Soliman H. Immunotherapy strategies in the treatment of breast cancer. Cancer Contr 2013; 20(1): 17-21.
Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol 2006; 6(5): 343-57.
Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 2008; 26(17): 2916-24.
Nezafat N, Ghasemi Y, Javadi G, Khoshnoud MJ, Omidinia E. A novel multi-epitope peptide vaccine against cancer: an in silico approach. J Theor Biol 2014; 349: 121-34.
Farhani I, Nezafat N, Mahmoodi S. Designing a Novel Multi-epitope Peptide Vaccine Against Pathogenic Shigella spp. Based Immunoinformatics Approaches. Int J Pept Res Ther 2018; 1-13.
Dougan M, Dranoff G. Immunotherapy of cancer. Innate immune regulation and cancer mmunotherapy 2012; 391-414.
Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 2002; 99(3): 754-8.
Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote of. the DNA damage response radioresistance by preferential activation. Nature 2006; 444(7120): 756-60.
Fransen MF, Sluijter M, Morreau H, Arens R, Melief CJ. Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin Cancer Res 2011; 17(8): 2270-80.
Toussi DN, Massari P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines 2014; 2(2): 323-53.
Gao JX. Cancer stem cells: the lessons from pre-cancerous stem cells. J Cell Mol Med 2008; 12(1): 67-96.
Huang EH, Heidt DG, Li C-W, Simeone DM. Cancer stem cells: a new paradigm for understanding tumor progression and therapeutic resistance. Surgery 2007; 141(4): 415-9.
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8(10): 755-68.
Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F, Kalthoff H. Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int 2007; 6(1): 92-7.
Wu CJ. Immunologic targeting of the cancer stem cell. Boston: IOS press 2008.
Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012; 6(10): 717-28.
Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015; 16(3): 225-38.
Xia T, Jiang H, Li C, Tian M, Zhang H. Molecular imaging in tracking tumor stem-like cells. BioMed Res Int 2012.
Huang S, Li Y, Chen Y, et al. Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1 transgenic mice. Genome Biol 2005; 6(10): 1.
Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis 2005; 26(4): 703-11.
Pannuti A, Foreman K, Rizzo P, et al. Targeting Notch to target cancer stem cells. Clin Cancer Res 2010; 16(12): 3141-52.
Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012; 44(10): 1111-6.
Vervoort S, van Boxtel R, Coffer P. The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe&quest. Oncogene 2013; 32(29): 3397-409.
Friedman RS, Bangur CS, Zasloff EJ, et al. Molecular and immunological evaluation of the transcription factor SOX-4 as a lung tumor vaccine antigen. The Journal of Immunology 2004; 172(5): 3319-27.
Pevny LH, Nicolis SK. Sox2 roles in neural stem cells. Int J Biochem Cell Biol 2010; 42(3): 421-4.
Castillo SD, Sanchez-Cespedes M. The SOX family of genes in cancer development: biological relevance and opportunities for therapy. Expert Opin Ther Targets 2012; 16(9): 903-19.
Arribillaga E, Alberdi M, Hernandez-Garcia S, et al. Expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012; 31(11): 1354-65.
Weina K, Utikal J. SOX2 and cancer: current research and its implications in the clinic. Clin Transl Med 2014; 3(1): 19.
Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1(5): 555-67.
Woodward WA, Sulman EP. Cancer stem cells: markers or biomarkers? Cancer Metastasis Rev 2008; 27(3): 459-70.
Dy P, Penzo-Mendez A, Wang H, Pedraza CE, Macklin WB, Lefebvre V. The three Sox11, Sox4 and Sox12 proteins exhibit overlapping expression patterns and molecular properties. Nucleic Acids Res 2008; 36(9): 3101-17.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon cancer-initiating cells. Nature 2007; 445(7123): 111-5.
Tsukahara T, Hirohashi Y, Kanaseki T, et al. Peptide vaccination therapy: Towards the next generation. Pathol Int 2016; 66(10): 547-53.
Relation T, Dominici M, Horwitz EM. Concise review: An (Im) Penetrable shield: How the tumor microenvironment protects cancer stem cells. Stem Cells 2017; 35(5): 1123-30.
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitor. Br J Cancer 2018; 118(1): 9-16.
Shmelkov SV, Clair RS, Lyden D, Rafii S. AC133/CD133/Prominin-1. Int J Biochem Cell Biol 2005; 37(4): 715-9.
Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea a paradigm shift. Cancer Res 2006; 66(4): 1883-90.
Klonisch T, Wiechec E, Hombach-Klonisch S, et al. Cancer stem cell markers in common cancers therapeutic implications. Trends Mol Med 2008; 14(10): 450-60.
Bao S, Wu Q, Li Z, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 2008; 68(15): 6043-8.
Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 2006; 351(4): 820-4.
Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367(6464): 645.
Zagozdzon R, Golab J. Cancer stem cells in haematological malignancies. Contemp Oncol 2015; 19(1): 1-10.
Servat J. Codony, clinical implications: Cancer stem cells and immunoresistance. Transl Lung Cancer Res 2015; 4(6): 689.
Han J, Fujisawa T, Husain SR, Puri RK. Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma. BMC Cancer 2014; 14(1): 173.
Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009; 27(5): 1006-20.
Akatsuka Y, Nishida T, Kondo E, et al. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J Exp Med 2003; 197(11): 1489-500.
Schatton T, Murphy GF, Frank NY, et al. Identification of cells initiating human melanomas. Nature 2008; 451(7176): 345-9.
Du X, Ho M, Pastan I. New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells. J Immunother 2007; 30(6): 607-13.
Smith L, Nesterova A, Ryan M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 2008; 99(1): 100-9.
Du L, Wang H, He L, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res 2008; 14(21): 6751-60.
Clay MR, Tabor M, Owen JH, et al. Single‐marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck 2010; 32(9): 1195-201.
Choi D, Lee HW, Hur KY, et al. Cancer stem cell markers CD133 and CD24 correlate with invasiveness and differentiation in colorectal adenocarcinoma. World J Gastroenterol 2009; 15(18): 2258-64.
Yang ZF, Ho DW, Ng MN, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008; 13(2): 153-66.
Chen Y, Yu D, Zhang H, et al. CD133 (+) EpCAM (+) phenotype possesses more characteristics of tumor initiating cells in hepatocellular carcinoma Huh7 cells. Int J Biol Sci 2012; 8(7): 992-1004.
Wang Y-C, Yo Y-T, Lee H-Y, et al. ALDH1-bright epithelial ovarian cancer cells are associated with CD44 expression, drug resistance, and poor clinical outcome. Am J Pathol 2012; 180(3): 1159-69.
Kagamu H, Nozaki K, Saida Y, et al. DEAD/H (Asp–Glu–Ala– Asp/His) box polypeptide 3, X-linked is an immunogenic target of cancer stem cells. Cancer Immunol Immunother 2013; 62(10): 1619-28.
Matsangou M, He B, You L, et al. A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia 2004; 6(1): 7-14.
Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene 2008; 27(3): 5124-31.
Gutheil JC, Campbell TN, Pierce PR, et al. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin ανβ3. Clin Cancer Res 2000; 6(8): 3056-61.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445(7123): 111.
Yang X-F. Immunology of stem cells and cancer stem cells. Cell Mol Immunol 2007; 4(3): 71-161.
dos Santos RV, da Silva LM. A possible explanation for the variable frequencies of cancer stem cells in tumors. PLoS One 2013; 8(8): 69-131.
Wood KJ, Issa F, Hester J. Understanding Stem Cell Immunogenicity in Therapeutic Applications. Trends Immunol 2016; 37(1): 5-16.
Dillman RO, Cornforth AN, Nistor G. Cancer stem cell antigen-based vaccines: the preferred strategy for active specific immunotherapy of metastatic melanoma? Expert Opin Biol Ther 2013; 13(5): 643-56.
Pattabiraman DR, Weinberg RA. Tackling the cancer stem cells what challenges do they pose? Nat Rev Drug Discov 2014; 13(7): 497-512.
Maccalli C, Volonte A, Cimminiello C, Parmiani G. Immunology of cancer stem cells in solid tumours. A review. Eur J Cancer 2014; 50(3): 649-55.
Frank NY, Margaryan A, Huang Y, et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005; 65(10): 4320-33.
Yilmaz ÖH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441(7092): 475.
Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest 2010; 120(1): 41-50.
Bao S, Wu Q, Sathornsumetee S, et al. Stem cell–like glioma cells factor promote tumor angiogenesis through vascular endothelial growth. Cancer Res 2006; 66(16): 7843-8.
Pellegatta S, Poliani PL, Corno D, et al. Neurospheres enriched in cancer stem–like cells are highly effective in eliciting a dendritic cell–mediated immune response against malignant gliomas. Cancer Res 2006; 66(21): 10247-52.
Mahmoodi S, Nezafat N, Barzegar A, et al. Harnessing bioinformatics for designing a novel multi-epitope peptide vaccine against breast cancer. Curr Pharm Biotechnol 2016; 17: 1100-14.
Nezafat N, Sadraeian M, Rahbar MR, et al. Production of a novel multi-epitope peptide vaccine for cancer immunotherapy in TC-1 tumor-bearing mice. Biologicals 2015; 43(1): 1-7.
Mahmoodi S, Nezafat N, Sarmadi S, Zarghami N, Ghasemi Y. Expression and purification of a novel multi-epitope peptide vaccine for breast cancer immunotherapy. Minerva Biotecnol 2017; 29(1): 1-7.
Dannull J, Diener P-A, Prikler L, Fürstenberger G, et al. Prostate stem cell antigen is a promising candidate for immunotherapy of advanced prostate cancer. Cancer Res 2000; 60(19): 5522-8.
Gu Z, Thomas G, Yamashiro J, et al. Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene 2000; 19(10): 1288.
Lee C-J, Appleby VJ, Orme AT, Chan W-I, Scotting PJ. Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 2002; 57(3): 201-14.
Lund AH, Turner G, Trubetskoy A, et al. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet 2002; 32(1): 160-5.
Schmitz M, Temme A, Senner V, et al. Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 2007; 96(8): 1293-301.
Xu Q, Liu G, Yuan X, et al. Antigen‐specific T‐cell response from dendritic cell vaccination using cancer stem‐like cell‐associated antigens. Stem Cells 2009; 27(8): 1734-40.
Deonarain MP, Kousparou CA, Epenetos AA. Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs 2009; 1: 12-25.
Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy. Cancer 2007; 109(2): 170-9.
Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates acute myeloid leukemic stem cells human. Nat Med 2006; 12(10): 1167-74.
Tijink BM, Buter J, de Bree R, et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res 2006; 12(20): 6064-72.
Oberneder R, Weckermann D, Ebner B, et al. A phase I study with adecatumumab, a human antibody directed against epithelial cell adhesion molecule, in hormone refractory prostate cancer patients. Eur J Cancer 2006; 42(15): 2530-8.
Ammons WS, Bauer RJ, Horwitz AH, Chen ZJ, Bautista E, Ruan HH, et al. In vitro and in vivo pharmacology and pharmacokinetics of a human engineered™ monoclonal antibody to epithelial cell adhesion molecule. Neoplasia 2003; 5(2): 146-54.
Sagiv E, Starr A, Rozovski U, et al. Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res 2008; 68(8): 2803-12.
Roberts A, He S, Ritchie D, et al. A phase I study of anti- CD123 monoclonal antibody (mAb) CSL360 targeting leukemia stem cells (LSC) in AML. ASCO Annual Meeting Proceedings. J Clin Oncol 2010. 28(15_suppl): e13012- e13012.
Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 2010; 16: 474-85.
Ning N, Pan Q, Zheng F, et al. Cancer Stem Cell Vaccination Confers Significant Antitumor Immunity. Cancer Res 2012; 72(7): 1853-64.
Duarte S, Momier D, Baqué P, et al. Preventive Cancer Stem Cell‐Based Vaccination Reduces Liver Metastasis Development in a Rat Colon Carcinoma Syngeneic Model. Stem Cells 2013; 31(3): 423-32.
Shih J, Rahman M, Luong QT, et al. Dominant B-cell epitopes from cancer/stem cell antigen SOX2 recognized by serum samples from cancer patients. Am J Clin Exp Immunol 2014; 3(2): 84.
Deng Z, Wu Y, Ma W, Zhang S, Zhang Y-Q. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol 2015; 16(1): 1.
Miyamoto S, Kochin V, Kanaseki T, et al. The antigen ASB4 on cancer stem cells serves as a target for CTL immunotherapy of colorectal cancer. Cancer Immunol Res 2018; 6: 358-69.
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10(9): 909-15.

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