Another phase I clinical trial using a peptide vaccine against VEGFR-1 was performed for advanced solid tumors, and activation of peptide-specific CTLs was also demonstrated . Over UNC1215 80% of gliomas are astrocytic tumors, including glioblastoma (GBM), the most malignant Rabbit Polyclonal to PHLDA3 glioma . Gliomas are characterized by their infiltrating nature, and extensive invasion into the surrounding normal brain tissue is often observed. Despite advances in treatment strategies, the prognosis for GBM patients remains very poor, and the resistance of GBM against treatment causes a high rate of tumor recurrence. The cancer stem cell (CSC) hypothesis provides an explanation for the therapeutic resistance and ability to regenerate tumors from a small population of cells. According to this hypothesis, only CSCs exhibiting stem-like characteristics can propagate and reinitiate the tumor. Recent studies support the existence of CSCs in GBM [2, 3], and a small number of glioma stem cells (GSCs) with resistances against conventional chemotherapy and UNC1215 radiotherapy are sufficient to give rise to recurrent tumors . In addition, because of their ability for multipotent differentiation and tumor initiation, GSCs can generate heterogeneous tumor masses as GBM. Since the discovery of GSCs, research for the treatment of GBM has focused on the identification of intrinsic molecular pathways involved in regulation of their stemness and tumorigenicity. However, it has become clear that GSCs are tightly regulated by specialized microenvironments (niches) within tumors, namely, vascular and hypoxic niches . Furthermore, GSCs do not simply receive signals from the surrounding niche but are also capable of modulating their niches through complex crosstalk . GSCs play a key role in shaping vascular niches through hypoxia-dependent stimulation of new blood vessel formation (angiogenesis), recruitment of endothelial progenitor cells, and direct trans-differentiation into endothelial cells. Furthermore, GSCs and the vascular niche represent integral parts of the tumor, which facilitate invasion and expansion. Therefore, understanding the interactions between GSCs and their niche is important for new therapeutic approaches. Recently, various immunotherapies have been attempted and some clinical studies have shown promising efficacy for the treatment of GBM [7C12]. In particular, cancer vaccines with epitope peptides for induction of cytotoxic T lymphocyte (CTL) responses in patients have shown encouraging results. Because GSCs are resistant to chemotherapy, more investigators are turning to immunotherapeutic strategies that target GSCs. Recent preclinical studies have also shown the effectiveness of immunotherapies targeting GSCs [13C16]. To design a rational immunotherapy against GBM, clear knowledge of GSCs and their niches is required. This review describes recent findings UNC1215 UNC1215 related to GSCs and their niches, as well as immunotherapies for treating glioma, followed by discussion of new immunotherapeutic strategies that target GSCs and their niche. 2. Glioma Gliomas are the most frequent primary tumor that arises in the brain, and the World Health Organization (WHO) classifies gliomas according to different grades of malignancy (ICIV) . Malignant gliomas are generally high grade (III and IV) in the WHO classification and the most malignant form of glioma is GBM. GBMs are heterogeneous tumors in both appearance and gene expression and exhibit the greatest range of genetic abnormalities. Recent genomic studies have revealed a set of core signaling pathways commonly activated in GBM, namely, p53, retinoblastoma, and receptor tyrosine kinase pathways [18, 19]. Moreover, The Cancer Genome Atlas project has provided somatic mutation information that revealed potential new roles for known tumor suppressors/oncogenes in GBM as well as new cancer driver genes. According to differences in clinical courses and their gene expression profiles, UNC1215 GBMs are subclassified into primary and secondary GBMs [20, 21], although the histology of both types of GBM is identical. Primary GBM occurs.