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      Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas

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          Abstract

          Background

          Immunotherapies targeting glioblastoma (GBM) have led to significant improvements in patient outcomes. TOX is closely associated with the immune environment surrounding tumors, but its role in gliomas is not fully understood.

          Methods

          Using data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we analyzed the transcriptomes of 1691 WHO grade I-IV human glioma samples. The R language was used to perform most of the statistical analyses. Somatic mutations and somatic copy number variation (CNV) were analyzed using GISTIC 2.0.

          Results

          TOX was down-regulated in malignant gliomas compared to low grade gliomas, and upregulated in the proneural and IDH mutant subtypes of GBM. TOX low tumours are associated with the loss of PTEN and amplification of EGFR, while TOX high tumours harbor frequent mutations in IDH1 (91%). TOX was highly expressed in leading edge regions of tumours. Gene ontology and pathway analyses demonstrated that TOX was enriched in multiple immune related processes including lymphocyte migration in GBM. Finally, TOX had a negative association with the infiltration of several immune cell types in the tumour microenvironment.

          Conclusion

          TOX has the potential to be a new prognostic marker for GBM.

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          Most cited references32

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          Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

          Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.
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            Immune microenvironment of gliomas

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              Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

              Background. Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. Methods. In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma ( n = 327), including glioblastoma (GBM) ( n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR ( MLH1 , MSH2 , MSH6 , and PMS2 ) protein expression and mutations, and DNA polymerase epsilon ( POLE ) mutations. Results. High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) ( P = . 0345), mutS homolog 2 (MSH2) ( P = . 0099), MSH6 ( P = . 0022), and postmeiotic segregation increased 2 (PMS2) ( P = . 0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. Conclusions. To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.
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                Author and article information

                Contributors
                zhangliyang@csu.edu.cn
                zhixiongliu@csu.edu.cn
                chengquan@csu.edu.cn
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                6 August 2020
                6 August 2020
                2020
                : 18
                : 305
                Affiliations
                [1 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Department of Neurosurgery, , Xiangya Hospital, Central South University, ; Changsha, 410008 Hunan People’s Republic of China
                [2 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Department of Clinical Pharmacology, , Xiangya Hospital, Central South University, ; Changsha, 410008 Hunan People’s Republic of China
                [3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Center for Medical Genetics and Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, ; Changsha, China
                [4 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, National Clinical Research Center for Geriatric Disorders, , Xiangya Hospital, Central South University, ; Changsha, Hunan China
                [5 ]GRID grid.266902.9, ISNI 0000 0001 2179 3618, Department of Medicine, , The University of Oklahoma Health Sciences Center, ; Oklahoma City, OK 73104 USA
                [6 ]GRID grid.452223.0, ISNI 0000 0004 1757 7615, Clinical Diagnosis and Therapeutic Center of Glioma, , Xiangya Hospital, Central South University, ; Changsha, 410078 Hunan People’s Republic of China
                Author information
                http://orcid.org/0000-0003-2401-5349
                Article
                2460
                10.1186/s12967-020-02460-3
                7409670
                32762688
                31932f55-15ea-433c-98b6-153be26f838a
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 7 February 2020
                : 26 July 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81472693
                Award ID: 81703622
                Award ID: 81873635
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100010031, Postdoctoral Research Foundation of China;
                Award ID: 2018M633002
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004735, Natural Science Foundation of Hunan Province;
                Award ID: 2018JJ3838
                Award Recipient :
                Funded by: Hunan provincial health and Health Committee Foundation of China
                Award ID: C2019186
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002767, Hunan Provincial Science and Technology Department;
                Award ID: 2015SK2032-2
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Medicine
                glioma,tox,inflammatory activity,immune response,prognosis
                Medicine
                glioma, tox, inflammatory activity, immune response, prognosis

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