Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors

References

• Bocangel DB, Finkelstein S, Schold SC, Bhakat KK, Mitra S, Kokkinakis DM. Multifaceted resistance of gliomas to temozolomide. Clin Cancer Res. 2002;8:2725–2734.
   PubMed Web of Science ®Google Scholar
• Sahm F, Capper D, Jeibmann A, Habel A, Paulus W, Troost D, von Deimling A. Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch Neurol. 2012;69(4):523–526. doi:10.1001/archneurol.2011.2910.
   PubMedGoogle Scholar
• Shu HK, Kim MM, Chen P, Furman F, Julin CM, Israel MA. The intrinsic radioresistance of glioblastoma-derived cell lines is associated with a failure of p53 to induce p21(BAX) expression. Proc Natl Acad Sci U S A. 1998;95(24):14453–14458. doi:10.1073/pnas.95.24.14453.
   PubMed Web of Science ®Google Scholar
• Stupp R, Mason WP, van Den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. doi:10.1056/NEJMoa043330.
   PubMed Web of Science ®Google Scholar
• Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. Jama. 2017;318(23):2306–2316. doi:10.1001/jama.2017.18718.
   PubMed Web of Science ®Google Scholar
• Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E, Creighton C. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One. 2009;4(11):e7752. doi:10.1371/journal.pone.0007752.
   PubMed Web of Science ®Google Scholar
• Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM, et al. Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene. 2003;22(15):2361–2373. doi:10.1038/sj.onc.1206344.
   PubMed Web of Science ®Google Scholar
• Verhaak RGW, 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(1):98–110. doi:10.1016/j.ccr.2009.12.020.
   PubMed Web of Science ®Google Scholar
• Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–173. doi:10.1016/j.ccr.2006.02.019.
   PubMed Web of Science ®Google Scholar
• Gill BJ, Pisapia DJ, Malone HR, Goldstein H, Lei L, Sonabend A, Yun J, Samanamud J, Sims JS, Banu M, et al. MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc Natl Acad Sci U S A. 2014;111(34):12550–12555. doi:10.1073/pnas.1405839111.
   PubMed Web of Science ®Google Scholar
• Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, et al. Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment. Cancer Cell. 2017;32(1):42-56.e6. doi: 10.1016/j.ccell.2017.06.003.
   Google Scholar
• Sturm D, Witt H, Hovestadt V, Khuong-Quang D-A, Jones DTW, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22(4):425–437. doi:10.1016/j.ccr.2012.08.024.
   PubMed Web of Science ®Google Scholar
• Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (New York, NY). 2014;344(6190):1396–1401. doi:10.1126/science.1254257.
   Google Scholar
• Hambardzumyan D, Bergers G. Glioblastoma: defining tumor niches. Trends Cancer. 2015;1(4):252–265. doi:10.1016/j.trecan.2015.10.009.
   PubMed Web of Science ®Google Scholar
• Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–27. doi:10.1038/nn.4185.
   PubMed Web of Science ®Google Scholar
• Feng X, Szulzewsky F, Yerevanian A, Chen Z, Heinzmann D, Rasmussen RD, Alvarez-Garcia V, Kim Y, Wang B, Tamagno I, et al. Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis. Oncotarget. 2015;6(17):15077–15094. doi:10.18632/oncotarget.3730.
   PubMedGoogle Scholar
• Hu F, A Dzaye OD, Hahn A, Yu Y, Scavetta RJ, Dittmar G, Kaczmarek AK, Dunning KR, Ricciardelli C, Rinnenthal JL, et al. Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling. Neuro-oncology. 2015;17(2):200–210. doi:10.1093/neuonc/nou324.
   PubMed Web of Science ®Google Scholar
• Morantz RA, Wood GW, Foster M, Clark M, Gollahon K. Macrophages in experimental and human brain tumors. Part 2: Studies of the Macrophage Content of Human Brain Tumors. J Neurosurg. 1979;50:305–311.
   PubMed Web of Science ®Google Scholar
• Rossi ML, Hughes JT, Esiri MM, Coakham HB, Brownell DB. Immunohistological study of mononuclear cell infiltrate in malignant gliomas. Acta Neuropathol. 1987;74:269–277.
   PubMed Web of Science ®Google Scholar
• Chen Z, Hambardzumyan D. Immune microenvironment in glioblastoma subtypes. Front Immunol. 2018;9:1004. doi:10.3389/fimmu.2018.01004.
   PubMed Web of Science ®Google Scholar
• Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science (New York, NY). 2010;330(6005):841–845. doi:10.1126/science.1194637.
   Google Scholar
• Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nature Rev Immunol. 2011;11(11):762–774. doi:10.1038/nri3070.
   PubMed Web of Science ®Google Scholar
• Schluesener HJ, Seid K, Kretzschmar J, Meyermann R. Allograft-inflammatory factor-1 in rat experimental autoimmune encephalomyelitis, neuritis, and uveitis: expression by activated macrophages and microglial cells. Glia. 1998;24:244–251.
   PubMed Web of Science ®Google Scholar
• Okano T, Nakagawa T, Kita T, Kada S, Yoshimoto M, Nakahata T, Ito J. Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea. J Neurosci Res. 2008;86(8):1758–1767. doi:10.1002/jnr.21625.
   PubMed Web of Science ®Google Scholar
• Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S. Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci. 2000;113:3073–3084.
   PubMed Web of Science ®Google Scholar
• Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau LM. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603–1615. doi:10.1158/1078-0432.CCR-10-2563.
   PubMed Web of Science ®Google Scholar
• Yang I, Tihan T, Han SJ, Wrensch MR, Wiencke J, Sughrue ME, Parsa AT. CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J Clin Neurosci. 2010;17(11):1381–1385. doi:10.1016/j.jocn.2010.03.031.
   PubMed Web of Science ®Google Scholar
• Rutledge WC, Kong J, Gao J, Gutman DA, Cooper LAD, Appin C, Park Y, Scarpace L, Mikkelsen T, Cohen ML, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res. 2013;19(18):4951–4960. doi:10.1158/1078-0432.CCR-13-0551.
   PubMed Web of Science ®Google Scholar
• Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M, Heimberger AB. Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res. 2013;1(2):112–122. doi:10.1158/2326-6066.CIR-13-0028.
   PubMed Web of Science ®Google Scholar
• Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32(1):42–56.e6. doi:10.1016/j.ccell.2017.06.003.
   PubMed Web of Science ®Google Scholar
• Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109. doi:10.1007/s00401-007-0243-4.
   PubMed Web of Science ®Google Scholar
• Kastenhuber ER, Huse JT, Berman SH, Pedraza A, Zhang J, Suehara Y, Viale A, Cavatore M, Heguy A, Szerlip N, et al. Quantitative assessment of intragenic receptor tyrosine kinase deletions in primary glioblastomas: their prevalence and molecular correlates. Acta Neuropathol. 2014;127(5):747–759. doi:10.1007/s00401-013-1217-3.
   PubMed Web of Science ®Google Scholar
• Xie Y, Bergström T, Jiang Y, Johansson P, Marinescu VD, Lindberg N, Segerman A, Wicher G, Niklasson M, Baskaran S, et al. The human glioblastoma cell culture resource: validated cell models representing all molecular subtypes. EBioMedicine. 2015;2(10):1351–1363. doi:10.1016/j.ebiom.2015.08.026.
   PubMed Web of Science ®Google Scholar
• Omuro A, Beal K, Gutin P, Karimi S, Correa DD, Kaley TJ, DeAngelis LM, Chan TA, Gavrilovic IT, Nolan C, et al. Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res. 2014;20(19):5023–5031. doi:10.1158/1078-0432.CCR-14-0822.
   PubMed Web of Science ®Google Scholar
• Lohr J, Ratliff T, Huppertz A, Ge Y, Dictus C, Ahmadi R, Grau S, Hiraoka N, Eckstein V, Ecker RC, et al. Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-β. Clin Cancer Res. 2011;17(13):4296–4308. doi:10.1158/1078-0432.CCR-10-2557.
   PubMed Web of Science ®Google Scholar
• Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–682. doi:10.1038/nmeth.2019.
   PubMed Web of Science ®Google Scholar
• Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–404. doi:10.1158/2159-8290.CD-12-0095.
   PubMed Web of Science ®Google Scholar
• Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1–pl1. doi:10.1126/scisignal.2004088.
   PubMed Web of Science ®Google Scholar
• Engler JR, Robinson AE, Smirnov I, Hodgson JG, Berger MS, Gupta N, James CD, Molinaro A, Phillips JJ, Jones C. Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS One. 2012;7(8):e43339. doi:10.1371/journal.pone.0043339.
   PubMed Web of Science ®Google Scholar
• Beier CP, Kumar P, Meyer K, Leukel P, Bruttel V, Aschenbrenner I, Riemenschneider MJ, Fragoulis A, Rümmele P, Lamszus K, et al. The cancer stem cell subtype determines immune infiltration of glioblastoma. Stem Cells Dev. 2012;21(15):2753–2761. doi:10.1089/scd.2011.0660.
   PubMed Web of Science ®Google Scholar
• Sørensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW. Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol. 2018;44(2):185–206. doi:10.1111/nan.12428.
   PubMed Web of Science ®Google Scholar
• Papageorgiou IE, Fetani AF, Lewen A, Heinemann U, Kann O. Widespread activation of microglial cells in the hippocampus of chronic epileptic rats correlates only partially with neurodegeneration. Brain Struct Funct. 2015;220(4):2423–2439. doi:10.1007/s00429-014-0802-0.
   PubMed Web of Science ®Google Scholar
• Sierra A, de Castro F, Del Rio-Hortega J, Rafael Iglesias-Rozas J, Garrosa M, Kettenmann H. The “Big-Bang” for modern glial biology: translation and comments on Pio del Rio-Hortega 1919 series of papers on microglia. Glia. 2016;64(11):1801–1840. doi:10.1002/glia.23046.
   PubMed Web of Science ®Google Scholar
• Wogram E, Wendt S, Matyash M, Pivneva T, Draguhn A, Kettenmann H. Satellite microglia show spontaneous electrical activity that is uncorrelated with activity of the attached neuron. Eur J Neurosci. 2016;43(11):1523–1534. doi:10.1111/ejn.13256.
   PubMed Web of Science ®Google Scholar
• Chen Z, Ross JL, Hambardzumyan D. Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages. Proc Natl Acad Sci U S A. 2019. doi:10.1073/pnas.1902366116.
   Web of Science ®Google Scholar
• Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91(2):461–553. doi:10.1152/physrev.00011.2010.
   PubMed Web of Science ®Google Scholar
• Lanier LL, Chang C, Spits H, Phillips JH. Expression of cytoplasmic CD3 epsilon proteins in activated human adult natural killer (NK) cells and CD3 gamma, delta, epsilon complexes in fetal NK cells. Implications for the relationship of NK and T lymphocytes. J Immunol (Baltimore, Md: 1950). 1992;149:1876–1880.
   PubMed Web of Science ®Google Scholar
• Han S, Zhang C, Li Q, Dong J, Liu Y, Huang Y, Jiang T, Wu A. Tumour-infiltrating CD4(+) and CD8(+) lymphocytes as predictors of clinical outcome in glioma. Br J Cancer. 2014;110(10):2560–2568. doi:10.1038/bjc.2014.162.
   PubMed Web of Science ®Google Scholar
• D’Acquisto F, Crompton T. CD3+CD4-CD8- (double negative) T cells: saviours or villains of the immune response? Biochem Pharmacol. 2011;82(4):333–340. doi:10.1016/j.bcp.2011.05.019.
   PubMed Web of Science ®Google Scholar
• Waziri A, Killory B, Ogden AT 3rd, Canoll P, Anderson RCE, Kent SC, Anderson DE, Bruce JN. Preferential in situ CD4+CD56+ T cell activation and expansion within human glioblastoma. J Immunol (Baltimore, Md: 1950). 2008;180(11):7673–7680. doi:10.4049/jimmunol.180.11.7673.
   PubMed Web of Science ®Google Scholar
• Muller A, Brandenburg S, Turkowski K, Muller S, Vajkoczy P. Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells. Int J Cancer. 2015;137(2):278–288. doi:10.1002/ijc.29379.
   PubMed Web of Science ®Google Scholar
• Chen Z, Feng X, Herting CJ, Alvarez Garcia V, Nie K, Pong WW, Rasmussen R, Dwivedi B, Seby S, Wolf SA, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017;77:2266–2278. doi:10.1158/0008-5472.CAN-16-2310.
   PubMed Web of Science ®Google Scholar
• Müller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, Watchmaker PB, Yagnik G, Di Lullo E, Malatesta M, et al. Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol. 2017;18(1):234. doi:10.1186/s13059-017-1362-4.
   PubMedGoogle Scholar
• Kmiecik J, Poli A, Brons NHC, Waha A, Eide GE, Enger PØ, Zimmer J, Chekenya M. Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol. 2013;264(1–2):71–83. doi:10.1016/j.jneuroim.2013.08.013.
   PubMed Web of Science ®Google Scholar
• Thomas AA, Fisher JL, Rahme GJ, Hampton TH, Baron U, Olek S, Schwachula T, Rhodes CH, Gui J, Tafe LJ, et al. Regulatory T cells are not a strong predictor of survival for patients with glioblastoma. Neuro-oncology. 2015;17(6):801–809. doi:10.1093/neuonc/nou363.
   PubMed Web of Science ®Google Scholar
• Yue Q, Zhang X, Ye H-X, Wang Y, Du Z-G, Yao Y, Mao Y. The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma. J Neurooncol. 2014;116(2):251–259. doi:10.1007/s11060-013-1314-0.
   PubMed Web of Science ®Google Scholar
• Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, Hiraoka N, Fuller GN. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res. 2008;14(16):5166–5172. doi:10.1158/1078-0432.CCR-08-0320.
   PubMed Web of Science ®Google Scholar
• Jacobs JFM, Idema AJ, Bol KF, Grotenhuis JA, de Vries IJ, Wesseling P, Adema GJ. Prognostic significance and mechanism of Treg infiltration in human brain tumors. J Neuroimmunol. 2010;225(1–2):195–199. doi:10.1016/j.jneuroim.2010.05.020.
   PubMed Web of Science ®Google Scholar
• Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. doi:10.1016/j.immuni.2009.03.019.
   PubMed Web of Science ®Google Scholar
• Zhai L, Ladomersky E, Lauing KL, Wu M, Genet M, Gritsina G, Győrffy 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(21):6650–6660. doi:10.1158/1078-0432.CCR-17-0120.
   PubMed Web of Science ®Google Scholar
• Platten M, Wick W. Tregs in gliomas - the jury is still out. Neuro-oncology. 2015;17(6):769–770. doi:10.1093/neuonc/nov034.
   PubMed Web of Science ®Google Scholar
• Vadasz Z, Toubi E. FoxP3 expression in macrophages, cancer, and B cells-is it real? Clin Rev Allergy Immunol. 2017;52(3):364–372. doi:10.1007/s12016-016-8572-5.
   PubMed Web of Science ®Google Scholar
• Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–522. doi:10.1016/j.ccr.2010.03.017.
   PubMed Web of Science ®Google Scholar
• Amankulor NM, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M, Margineantu DH, Rao A, Bolouri H, Delrow J, et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes Dev. 2017;31(8):774–786. doi:10.1101/gad.294991.116.
   PubMed Web of Science ®Google Scholar
• Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2018;33(1):152. doi:10.1016/j.ccell.2017.12.012.
   PubMed Web of Science ®Google Scholar
• Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723. doi:10.1056/NEJMoa1003466.
   PubMed Web of Science ®Google Scholar
• Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–2092. doi:10.1056/NEJMoa1801005.
   PubMed Web of Science ®Google Scholar
• Heiland DH, Haaker G, Delev D, Mercas B, Masalha W, Heynckes S, Gäbelein A, Pfeifer D, Carro MS, Weyerbrock A, et al. Comprehensive analysis of PD-L1 expression in glioblastoma multiforme. Oncotarget. 2017;8(26):42214–42225. doi:10.18632/oncotarget.15031.
   PubMedGoogle Scholar
• Nduom EK, Wei J, Yaghi NK, Huang N, Kong L-Y, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ, et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro-oncology. 2016;18(2):195–205. doi:10.1093/neuonc/nov172.
   PubMed Web of Science ®Google Scholar
• Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, Dieckmann K, Filipits M, Brandstetter A, Weller M, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-oncology. 2015;17(8):1064–1075. doi:10.1093/neuonc/nou307.
   PubMed Web of Science ®Google Scholar
• Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Conway AS, Liao X, Zhou J, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. 2016;4(2):124–135. doi:10.1158/2326-6066.CIR-15-0151.
   PubMed Web of Science ®Google Scholar
• Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, Albesiano E, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–349. doi:10.1016/j.ijrobp.2012.12.025.
   PubMed Web of Science ®Google Scholar
• Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–486. doi:10.1038/s41591-018-0337-7.
   PubMed Web of Science ®Google Scholar
• Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15(7):422–442. doi:10.1038/s41571-018-0003-5.
   PubMed Web of Science ®Google Scholar