Stem cell research has led to the discovery of glioma stem cells (GSCs), and because these cells are resistant to chemotherapy and radiotherapy, analysis of their properties has been rapidly pursued for targeted treatment of malignant glioma. Recent studies have also revealed complex crosstalk between GSCs and their specialized environment (niche). Therefore, targeting not only GSCs but also their niche may be a principle for novel therapies of malignant glioma. One possible novel strategy for targeting GSCs and their niches is immunotherapy with different antitumor mechanism(s) from those of conventional therapy. Recent clinical studies of immunotherapy using peptide vaccines and antibodies have shown promising results. This review describes the recent findings related to GSCs and their niches, as well as immunotherapies for glioma, followed by discussion of immunotherapies that target GSCs for the treatment of malignant glioma. 1. Introduction Gliomas are the most common histological type of malignant brain tumor and share the feature of having some degree of glial differentiation. Over 80% of gliomas are astrocytic tumors, including glioblastoma (GBM), the most malignant glioma [1]. 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 radiotherapy are sufficient to give rise to recurrent tumors [4]. 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 [5]. Furthermore, GSCs do not simply receive signals from the surrounding niche but
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