Human leukocyte antigen-G overexpression predicts poor clinical outcomes in low-grade gliomas
Graphical abstract
Introduction
Glioma, the most common and most lethal primary tumor of the central nervous system, accounts for more than 70% of all brain tumors (DeAngelis, 2001, Ohgaki and Kleihues, 2005). Gliomas are typically very difficult to resect completely, and often recur after surgery. Thus, they represent a challenge in neuro-oncology (DeAngelis, 2001, Ohgaki and Kleihues, 2005). For the most frequent and aggressive type of glioma, glioblastoma multiforme (GBM), the median duration of survival after standard treatment with maximal surgical resection and subsequent radio-chemotherapy is only 14.6 months, and the two-year survival rate is below 30% (Stupp et al., 2009, Stupp et al., 2005). Although recent studies have contributed to the knowledge of gliomas, yet the molecular basis of this cancer needs to be fully elucidated.
Evasion of immune surveillance and suppression of the immune system are hallmarks of cancer. Schreiber first proposed and improved the concept of cancer immunoediting, which results from the interaction between innate and adaptive immune cells in the tumor microenvironment, local inflammation and the immune response of the host (Dunn et al., 2002, Vesely et al., 2011, Vesely and Schreiber, 2013). The concept of cancer immunoediting refers to the complex interaction between tumor cells and the immune system, and to the dual role of immune system in the development of cancer, i.e., both tumor suppression and tumor progression (Manjili, 2011, Mittal et al., 2014, Schreiber et al., 2011). Up to 20% of all clinical tumors are related to an underlying chronic inflammation, wherein the immune cells stimulate tumor growth and progression (Grivennikov et al., 2010). The immunosuppressive property of human glioma is well-characterized (Wiendl et al., 2002). However, the underlying mechanisms which allow it to evade the host immune system are not completely understood.
The major histocompatibility complex (MHC) refers to a group of coding genes for the cell surface proteins which modulate the immune response. The human MHC is also called human leukocyte antigen (HLA) complex. HLA gene is located at the 6p21.31 region on the short arm of human chromosome 6. It is a 4000 kb gene complex which consists of hundreds of gene groups. It is known for its maximum allelic polymorphisms and is closely related to the regulation of human immune system (Reipert, 2014, Rouas-Freiss et al., 2003). Based on the gene sequence, it is generally divided into three groups: HLA-I (e.g., HLA-A, HLA-B, HLA-C, HLA-E, and HLA-G), HLA-II (e.g., HLA-DR, HLA-DP, and HLA-DQ) and HLA-III (Nakajima et al., 2010). Altered expression of HLA has been documented in a variety of inflammatory or malignant conditions. The association of HLA expression with certain human diseases has also been demonstrated. For instance, in the early 1970's a strong correlation between HLA-B27 and ankylosing spondylitis was detected in more than 90% patients (Schlosstein et al., 1973). Similar association has also been demonstrated between HLA and human cancers (e.g. cervical cancer and breast cancer) (Jia et al., 2015, Kochan et al., 2013).
The association between glioma and HLA gene expression has been reported. A positive correlation between HLA-E expression and survival status was found in patients with glioblastoma (Kren et al., 2011). In a recent study, overexpression of HLA-DR was shown to be associated with poor prognosis in glioma patients (Diao et al., 2015). In our previous study, we identified an association between HLA-G expression and radiologic morphology in low-grade gliomas (LGGs) (Wang et al., 2015). To the best of our knowledge, no study has yet investigated the role HLA-G plays in different grades of gliomas. We assessed the mRNA expression level of HLA-G in glioma patients and explored its potential correlation with different clinicopathological parameters.
Section snippets
Patients and tissue samples
Gene microarray data pertaining to 293 patients with glioma was retrospectively analyzed. Surgically resected brain tissues obtained from 5 trauma patients served as negative controls. Histological diagnosis of gliomas was independently performed by two experienced neuropathologists according to the 2007 World Health Organization classification (Louis et al., 2007). The tumor tissues were obtained from patients after surgical resection between June 2007 and September 2013 in the Department of
Patient characteristics
Clinical and mRNA expression microarray data for all 293 patients were obtained. Among these, 117 patients were staged as grade II (Low-grade glioma), 50 as grade III (Anaplastic glioma, AG) and 126 were staged as grade IV (Glioblastoma multiforme, GBM). At the time of diagnosis, the median age of subjects was 38 years (range 18–62 yrs). Baseline patient characteristics are summarized in Table 1.
Expression of HLA-G in gliomas of different grades
HLA-G expression in all different grades (II–IV) of glioma tissues was significantly higher as
Discussion
In the present study, we performed a retrospective analysis of clinical and mRNA expression microarray data pertaining to 220 patients with histologically confirmed gliomas. The mean expression levels of HLA-G were compared between patients with different grades of gliomas. Increased expression of HLA-G was associated with higher tumor grade in gliomas. Thus, elevated HLA-G expression may serve as an independent prognostic factor for poor clinical outcomes in patients with LGGs.
HLA-G is a
Conflict of interest
The authors have no actual or potential conflicts of interest related to this manuscript. Appropriate approval and procedures were used concerning human subjects.
Acknowledgments
This work was supported by funding from the National 973 Program (No. 2015CB755500), the National High Technology Research and Development Program (No. 2012AA02A508).
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