Brain Tumor Stem Cells and Immunotherapy


  • Isako Saga Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan
  • Masahiro Toda Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan



Glioma, glioblastoma, cancer stem cell, niche, immunoresistance, peptide vaccine, EGFRvIII, WT1, dendritic cell, SOX6.


 Glioblastoma multiforme (GBM) is one of the most common aggressive primary brain tumors, and it responds poorly to the current treatment combination of surgery, radio-, and chemotherapy. The hypothesis that cancer stem cells may account for the pathogenesis underlying various tumors, including GBM, has been accepted widely in recent years. Brain tumor stem cells (BTSCs) have been shown to contribute to therapeutic resistance and the presence of BTSCs may explain the recurrence of GBM following conventional treatment, as just a few BTSCs are sufficient to give rise to a new tumor. Therefore, the therapeutic targeting of BTSCs is of utmost importance. Among emerging treatment modalities, immunotherapy is a strategy that has the potential to target BTSCs that are resistant to conventional therapies. This review describes recent advancements in the study of BTSCs and immunotherapy.


Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10(5): 459-66.

Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3(7): 730-7.

Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63(18): 5821-8.

Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006; 9(5): 391-403.

Heimberger AB, Crotty LE, Archer GE, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 2003; 9(11): 4247-54.

Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010; 28(31): 4722-9.

Yajima N, Yamanaka R, Mine T, et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res 2005; 11(16): 5900-11.

Terasaki M, Shibui S, Narita Y, et al. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme. J Clin Oncol 2011; 29(3): 337-44.

Izumoto S, Tsuboi A, Oka Y, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 2008; 108(5): 963-71.

Iwami K, Shimato S, Ohno M, et al. Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor alpha2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele. Cytotherapy 2012.

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.

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.

Ueda R, Ohkusu-Tsukada K, Fusaki N, et al. Identification of HLA-A2- and A24-restricted T-cell epitopes derived from SOX6 expressed in glioma stem cells for immunotherapy. Int J Cancer 2010; 126(4): 919-29.

Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66(19): 9339-44.

Vescovi AL, Galli R, Reynolds BA. Brain tumour stem cells. Nat Rev Cancer 2006; 6(6): 425-36.

Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004; 432(7015): 396-401.

Pastrana E, Silva-Vargas V, Doetsch F. Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 2011; 8(5): 486-98.

Beier D, Hau P, Proescholdt M, et al. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 2007; 67(9): 4010-5.

Joo KM, Kim SY, Jin X, et al. Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas. Lab Invest 2008; 88(8): 808-15.

Chen R, Nishimura MC, Bumbaca SM, et al. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 2010; 17(4): 362-75.

Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 2009; 4(5): 440-52.

Lathia JD, Gallagher J, Heddleston JM, et al. Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 2010; 6(5): 421-32.

Anido J, Saez-Borderias A, Gonzalez-Junca A, et al. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010; 18(6): 655-68.

Ligon KL, Huillard E, Mehta S, et al. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 2007; 53(4): 503-17.

Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 2007; 17(2): 165-72.

Dahmane N, Sanchez P, Gitton Y, et al. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 2001; 128(24): 5201-12.

Ruiz i Altaba A, Stecca B, Sanchez P. Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 2004; 204(2): 145-57.

Zbinden M, Duquet A, Lorente-Trigos A, Ngwabyt SN, Borges I, Ruiz i Altaba A. NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53. EMBO J 2010; 29(15): 2659-74.

Po A, Ferretti E, Miele E, et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J 2010; 29(15): 2646-58.

Bruggeman SW, Hulsman D, Tanger E, et al. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007; 12(4): 328-41.

Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006; 66(15): 7445-52.

Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 2008; 22(4): 436-48.

Bleau AM, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 2009; 4(3): 226-35.

Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K. Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 2009; 5(5): 504-14.

Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006; 444(7120): 761-5.

Lee J, Son MJ, Woolard K, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008; 13(1): 69-80.

Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003; 113(5): 643-55.

Palma V, Lim DA, Dahmane N, et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 2005; 132(2): 335-44.

Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991; 65(5): 753-63.

van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991; 65(5): 737-52.

Zencak D, Lingbeek M, Kostic C, et al. Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci 2005; 25(24): 5774-83.

Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442(7104): 823-6.

Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M, Holland EC. mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 2005; 7(4): 356-68.

Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11(1): 69-82.

Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006; 66(16): 7843-8.

Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468(7325): 824-8.

Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010; 468(7325): 829-33.

Clarke L, van der Kooy D. Low oxygen enhances primitive and definitive neural stem cell colony formation by inhibiting distinct cell death pathways. Stem Cells 2009; 27(8): 1879-86.

Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 2009; 8(20): 3274-84.

Li Z, Bao S, Wu Q, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009; 15(6): 501-13.

Piccirillo SG, Combi R, Cajola L, et al. Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 2009; 28(15): 1807-11.

Roesch A, Fukunaga-Kalabis M, Schmidt EC, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010; 141(4): 583-94.

Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell 2009; 4(3): 203-5.

Barrett LE, Granot Z, Coker C, et al. Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma. Cancer Cell 2012; 21(1): 11-24.

Visvader JE. Cells of origin in cancer. Nature 2011; 469(7330): 314-22.

Medzhitov R, Janeway C, Jr. Innate immunity. N Engl J Med 2000; 343(5): 338-44.

Abbas AK, Janeway CA, Jr. Immunology: improving on nature in the twenty-first century. Cell 2000; 100(1): 129-38.

Pachter JS, de Vries HE, Fabry Z. The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol 2003; 62(6): 593-604.

Fabry Z, Raine CS, Hart MN. Nervous tissue as an immune compartment: the dialect of the immune response in the CNS. Immunol Today 1994; 15(5): 218-24.

Lampson LA, Hickey WF. Monoclonal antibody analysis of MHC expression in human brain biopsies: tissue ranging from "histologically normal" to that showing different levels of glial tumor involvement. J Immunol 1986; 136(11): 4054-62.

Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 2006; 80(4): 797-801.

Calzascia T, Masson F, Di Berardino-Besson W, et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 2005; 22(2): 175-84.

Yang I, Han SJ, Kaur G, Crane C, Parsa AT. The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 2010; 17(1): 6-10.

Albesiano E, Han JE, Lim M. Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am 2010; 21(1): 17-29.

Heimberger AB, Sampson JH. Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 2011; 13(1): 3-13.

Rolle CE, Sengupta S, Lesniak MS. Challenges in clinical design of immunotherapy trials for malignant glioma. Neurosurg Clin N Am 2010; 21(1): 201-14.

Wei J, Barr J, Kong LY, et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther 2010; 9(1): 67-78.

Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ. Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 2002; 169(5): 2253-63.

Mancino A, Lawrence T. Nuclear factor-kappaB and tumor-associated macrophages. Clin Cancer Res 2010; 16(3): 784-9.

Brantley EC, Benveniste EN. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res 2008; 6(5): 675-84.

Di Tomaso T, Mazzoleni S, Wang E, et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res 2010; 16(3): 800-13.

Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313(23): 1485-92.

Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995; 13(3): 688-96.

Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17(7): 2105-16.

Merchant RE, McVicar DW, Merchant LH, Young HF. Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-alpha. Results of a phase I clinical trial. J Neurooncol 1992; 12(1): 75-83.

Colombo F, Barzon L, Franchin E, et al. Combined HSV-TK/IL-2 gene therapy in patients with recurrent glioblastoma multiforme: biological and clinical results. Cancer Gene Ther 2005; 12(10): 835-48.

Wolff JE, Wagner S, Reinert C, et al. Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma. J Neurooncol 2006; 79(3): 315-21.

Allen J, Packer R, Bleyer A, Zeltzer P, Prados M, Nirenberg A. Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors. J Clin Oncol 1991; 9(5): 783-8.

Buckner JC, Schomberg PJ, McGinnis WL, et al. A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer 2001; 92(2): 420-33.<420::AID-CNCR1338>3.0.CO;2-3

Kikuchi T, Akasaki Y, Abe T, et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother 2004; 27(6): 452-9.

Bogdahn U, Hau P, Stockhammer G, et al. Targeted therapy for high-grade glioma with the TGF-beta2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol 2011; 13(1): 132-42.

Jaschinski F, Rothhammer T, Jachimczak P, Seitz C, Schneider A, Schlingensiepen KH. The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-beta2. Curr Pharm Biotechnol 2011; 12(12): 2203-13.

Hayes RL, Koslow M, Hiesiger EM, et al. Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer 1995; 76(5): 840-52.<840::AID-CNCR2820760519>3.0.CO;2-R

Itoh K, Sawamura Y, Hosokawa M, Kobayashi H. Scintigraphy with In-111 labeled lymphokine-activated killer cells of malignant brain tumor. Radiat Med 1988; 6(6): 276-81.

Kahlon KS, Brown C, Cooper LJ, Raubitschek A, Forman SJ, Jensen MC. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res 2004; 64(24): 9160-6.

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(2): 474-85.

van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254(5038): 1643-7.

Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001; 411(6835): 380-4.

Ardon H, Van Gool SW, Verschuere T, et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother 2012.

Schneider T, Gerhards R, Kirches E, Firsching R. Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 2001; 53(1): 39-46.

Steiner HH, Bonsanto MM, Beckhove P, et al. Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 2004; 22(21): 4272-81.

Ishikawa E, Tsuboi K, Yamamoto T, et al. Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci 2007; 98(8): 1226-33.

Yang I, Han S, Parsa AT. Heat-shock protein vaccines as active immunotherapy against human gliomas. Expert Rev Anticancer Ther 2009; 9(11): 1577-82.

See AP, Pradilla G, Yang I, Han S, Parsa AT, Lim M. Heat shock protein-peptide complex in the treatment of glioblastoma. Expert Rev Vaccines 2011; 10(6): 721-31.

Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10(9): 909-15.

Li G, Mitra S, Wong AJ. The epidermal growth factor variant III peptide vaccine for treatment of malignant gliomas. Neurosurg Clin N Am 2010; 21(1): 87-93.

Gan HK, Kaye AH, Luwor RB. The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 2009; 16(6): 748-54.

Heimberger AB, Archer GE, Crotty LE, et al. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery 2002; 50(1): 158-64; discussion 64-6.

Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 2008; 20(5): 267-75.

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987-96.

Mine T, Sato Y, Noguchi M, et al. Humoral responses to peptides correlate with overall survival in advanced cancer patients vaccinated with peptides based on pre-existing, peptide-specific cellular responses. Clin Cancer Res 2004; 10(3): 929-37.

Oka Y, Tsuboi A, Elisseeva OA, Udaka K, Sugiyama H. WT1 as a novel target antigen for cancer immunotherapy. Curr Cancer Drug Targets 2002; 2(1): 45-54.

Jarboe JS, Johnson KR, Choi Y, Lonser RR, Park JK. Expression of interleukin-13 receptor alpha2 in glioblastoma multiforme: implications for targeted therapies. Cancer Res 2007; 67(17): 7983-6.

Eguchi J, Hatano M, Nishimura F, et al. Identification of interleukin-13 receptor alpha2 peptide analogues capable of inducing improved antiglioma CTL responses. Cancer Res 2006; 66(11): 5883-91.

Saka M, Amano T, Kajiwara K, et al. Vaccine therapy with dendritic cells transfected with Il13ra2 mRNA for glioma in mice. J Neurosurg 2010; 113(2): 270-9.

Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444(7120): 756-60.

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.

Ueda R, Kinoshita E, Ito R, Kawase T, Kawakami Y, Toda M. Induction of protective and therapeutic antitumor immunity by a DNA vaccine with a glioma antigen, SOX6. Int J Cancer 2008; 122(10): 2274-9.




How to Cite

Isako Saga, & Masahiro Toda. (2012). Brain Tumor Stem Cells and Immunotherapy . Journal of Cancer Research Updates, 1(1),  28–38.