Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas

Authors: Peng-fei Wang, Hong-qing Cai, Chuan-bao Zhang, Yan-Michael Li, Xiang Liu, Jing-hai Wan, Tao Jiang, Shou-wei Li, Chang-Xiang Yan

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling.

Methods

Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures.

Results

PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas.

Conclusion

PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies.
Appendix
Available only for authorised users
Literature
1.
Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro-Oncology. 2016;18:v1–v75.CrossRefPubMed
2.
Woehrer A, Bauchet L, Barnholtz-Sloan JS. Glioblastoma survival: has it improved? Evidence from population-based studies. Curr Opin Neurol. 2014;27:666–74.PubMed
3.
Weber J, D'Angelo S, Minor D, Hodi F, Gutzmer R, Neyns B, Hoeller C, Khushalani N, Miller W, Lao C, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.CrossRefPubMed
4.
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.CrossRefPubMed
5.
McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, Brahmer JR, Carvajal RD, Hammers HJ, Puzanov I, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33:2013–20.CrossRefPubMedPubMedCentral
6.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.CrossRefPubMedPubMedCentral
7.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56.
8.
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, Linette GP, Meyer N, Giguere JK, Agarwala SS, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68.CrossRefPubMedPubMedCentral
9.
Wang Z, Zhang C, Liu X, Wang Z, Sun L, Li G, Liang J, Hu H, Liu Y, Zhang W. Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology. 2016;5:e1196310.
10.
Li G, Wang Z, Zhang C, Liu X, Cai J, Wang Z, Hu H, Wu F, Bao Z, Liu Y, et al. Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. Oncoimmunology. 2017;6:e1328339.CrossRefPubMedPubMedCentral
11.
Zhai L, Ladomersky E, Lauing KL, Wu M, Genet M, Gritsina G, Gyorffy B, Brastianos PK, Binder DC, Sosman JA, et al. Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival. Clin Cancer Res. 2017;23:6650–60.CrossRefPubMed
12.
Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E, Liu A, Sankey EW, Tam A, Xu H, et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin Cancer Res. 2017;23:124–36.CrossRefPubMed
13.
Pike KA, Tremblay ML. TC-PTP and PTP1B: regulating JAK-STAT signaling, controlling lymphoid malignancies. Cytokine. 2016;82:52–7.CrossRefPubMed
14.
Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet C, Galic S, Tremblay ML, Russell SM, Godfrey DI, Tiganis T. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758–74.CrossRefPubMedPubMedCentral
15.
Aradi B, Kato M, Filkova M, Karouzakis E, Klein K, Scharl M, Kolling C, Michel BA, Gay RE, Buzas EI, et al. Protein tyrosine phosphatase nonreceptor type 2: an important regulator of lnterleukin-6 production in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 2015;67:2624–33.CrossRefPubMed
16.
Scharl M, Hruz P, McCole DF. Protein tyrosine phosphatase non-receptor type 2 regulates IFN-gamma-induced cytokine signaling in THP-1 monocytes. Inflamm Bowel Dis. 2010;16:2055–64.CrossRefPubMed
17.
Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, Collins NB, Bi K, LaFleur MW, Juneja VR, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547:413–8.CrossRefPubMedPubMedCentral
18.
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRefPubMed
19.
Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C. Cutoff finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS One. 2012;7:e51862.CrossRefPubMedPubMedCentral
20.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.CrossRefPubMedPubMedCentral
21.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.CrossRefPubMed
22.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.CrossRefPubMedPubMedCentral
23.
Kok CH, Leclercq T, Watkins DB, Saunders V, Wang J, Hughes TP, White DL. Elevated PTPN2 expression is associated with inferior molecular response in de-novo chronic myeloid leukaemia patients. Leukemia. 2014;28:702–5.CrossRefPubMed
24.
Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11:R15.CrossRefPubMedPubMedCentral
25.
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14:399–416.CrossRefPubMedPubMedCentral
26.
Domingues P, Gonzalez-Tablas M, Otero A, Pascual D, Miranda D, Ruiz L, Sousa P, Ciudad J, Goncalves JM, Lopes MC, et al. Tumor infiltrating immune cells in gliomas and meningiomas. Brain Behav Immun. 2016;53:1–15.CrossRefPubMed
27.
28.
Zhang X, Zhu S, Li T, Liu YJ, Chen W, Chen J. Targeting immune checkpoints in malignant glioma. Oncotarget. 2017;8:7157–74.PubMed
29.
Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49.CrossRefPubMedPubMedCentral
30.
Wang Z, Zhang C, Liu X, Wang Z, Sun L, Li G, Liang J, Hu H, Liu Y, Zhang W, Jiang T. Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology. 2016;5:e1196310.CrossRefPubMedPubMedCentral
31.
Sharp RC, Abdulrahim M, Naser ES, Naser SA. Genetic variations of PTPN2 and PTPN22: role in the pathogenesis of type 1 diabetes and Crohn’s disease. Front Cell Infect Microbiol. 2015;5:95.CrossRefPubMedPubMedCentral
32.
Wiede F, Sacirbegovic F, Leong YA, Yu D, Tiganis T. PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity. J Autoimmun. 2017;76:85–100.CrossRefPubMed
33.
Wiede F, Ziegler A, Zehn D, Tiganis T. PTPN2 restrains CD8(+) T cell responses after antigen cross-presentation for the maintenance of peripheral tolerance in mice. J Autoimmun. 2014;53:105–14.CrossRefPubMed
34.
Pike KA, Hatzihristidis T, Bussieres-Marmen S, Robert F, Desai N, Miranda-Saavedra D, Pelletier J, Tremblay ML. TC-PTP regulates the IL-7 transcriptional response during murine early T cell development. Sci Rep. 2017;7:13275.CrossRefPubMedPubMedCentral
35.
Simoncic PD, Bourdeau A, Lee-Loy A, Rohrschneider LR, Tremblay ML, Stanley ER, McGlade CJ. T-cell protein tyrosine phosphatase (Tcptp) is a negative regulator of colony-stimulating factor 1 signaling and macrophage differentiation. Mol Cell Biol. 2006;26:4149–60.CrossRefPubMedPubMedCentral
36.
Zhang H, Liu H, Shen Z, Lin C, Wang X, Qin J, Qin X, Xu J, Sun Y. Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Ann Surg. 2018;267:311–8.CrossRefPubMed
37.
38.
39.
Lowther DE, Hafler DA. Regulatory T cells in the central nervous system. Immunol Rev. 2012;248:156–69.CrossRefPubMed
40.
Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J. Interferon-gamma-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology. 2015;4:e1008824.CrossRefPubMedPubMedCentral
41.
Wang X, Schoenhals JE, Li A, Valdecanas DR, Ye H, Zang F, Tang C, Tang M, Liu CG, Liu X, et al. Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy. Cancer Res. 2017;77:839–50.CrossRefPubMed
42.
Metadata
Title
Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas
Authors
Peng-fei Wang
Hong-qing Cai
Chuan-bao Zhang
Yan-Michael Li
Xiang Liu
Jing-hai Wan
Tao Jiang
Shou-wei Li
Chang-Xiang Yan
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1187-4

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial

Review

Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease

Research

High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats

Research

Profiling the proteomic inflammatory state of human astrocytes using DIA mass spectrometry

Research

Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy

Research

Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity