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Front Immunol ; 12: 679425, 2021.
Article in English | MEDLINE | ID: covidwho-1344264


Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients' survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body's effective anti-glioma immune response.

Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Glioma/drug therapy , Glioma/pathology , Immune Checkpoint Inhibitors/therapeutic use , Tumor Microenvironment/drug effects , Biomarkers, Tumor , Brain/drug effects , Brain/immunology , Brain/metabolism , Brain/pathology , Brain Neoplasms/etiology , Brain Neoplasms/mortality , Disease Susceptibility , Glioma/etiology , Glioma/mortality , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Proteins/genetics , Immune Checkpoint Proteins/metabolism , Molecular Targeted Therapy , Prognosis , Treatment Outcome , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
Immunity ; 54(1): 132-150.e9, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-957143


HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity.

Aspartic Acid Endopeptidases/metabolism , CD8-Positive T-Lymphocytes/immunology , Glioma/immunology , Glycosphingolipids/metabolism , Glycosyltransferases/metabolism , HLA Antigens/metabolism , Histocompatibility Antigens Class I/metabolism , Immunotherapy/methods , Antigen Presentation , Aspartic Acid Endopeptidases/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glioma/mortality , Glycosphingolipids/immunology , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , Humans , Lymphocyte Activation , Signal Transduction , Survival Analysis , Tumor Escape