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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۱۵-۱۵
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عنوان انگلیسی Is-15: Neuronal Program Death Ligand 1/PD-L1 Central in Limiting Glioblastoma
چکیده انگلیسی مقاله Objective: Activating the immune system to combat cancer has long been the focus of tumor immunologists. However the tumor microenvironment may impede immune responses, leading to ineffective or suboptimal tumor responses to immunotherapy. Therefore, understanding the immunosuppressive nature of the tumor microenvironment and stromal cells is essential for designing strategies that increase the likelihood of successful therapies and assist the tumor microenvironment in supporting beneficial immunity. Glioblastoma multiforme (GBM) is a highly invasive tumor characterized by rapid growth, dismal prognoses, and resistance to standard treatments, yet GBM is relatively rare among primary cancers. We assume that brain-specific stromal cells are equipped to guard tissue serenity, and we postulate that common defects in immunologic genes (Ifnb and Pdl1) or the instability of stromal cells may be central to the development of chronic inflammation and cancer progression. Materials and Methods: Surgical tissues from tumor mass and associated brain tissues were collected from patients with GBM. Immunoflorescent histochemistry was utilized to study differential expression of PD-L1 by neurons versus tumor cells. Experimental model of glioma was established in different gene modified mice. We utilize different blocking antibodies and or gene targeting techniques to knock out/overexpress genes or proteins in neurons to study their functions. We also utilized DNA microarray to identify differentially expressed genes in neurons. Results: Lack of IFNβ led to the loss of program cell death ligand 1 (PD-L1) expression by the neurons. PDL1 is a transmembrane protein and a negative regulator of T-cell activation via binding to known receptors (PD- 1 and B7-1). Our investigation revealed that neuronal PD-L1 is instrumental in limiting glioma growth by inducing caspase-dependent cell death. Additionally we found out that neuronal PD-L1 expression is associated with better prognosis in patients with GBM.Conclusion: It is likely that immunocompetent neurons (and other tissue-specific tumor stromal cells) sense and prevent tumor growth, partially through upregulation of IFNβ-dependent PD-L1, which binds to an unknown receptor on glioblastomas, thereby suppressing PD-L1 expression. Subsequently, this process results in tumor arrest by inducing caspase-dependent cell death. Neurons with immunogenetic defects, such as those lacking the Ifnb gene and its targets like pdl1, lack antitumor suppressive capacity. In this scenario, immunocompromised brain acts as a double-edged sword. It allows gliomagenesis and CNS inflammation, while it also tolerates tumor growth because neurons cannot engage immune receptors and hence are unable to induce tumor killing. The immune make up of the brain tissue versus tumors should be considered carefully to select suitable immunetherapy.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/309
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