Drug resistance in glioblastoma: from chemo- to immunotherapy

Abstract

As the most common and aggressive type of primary brain tumor in adults, glioblastoma is estimated to end over 10,000 lives each year in the United States alone. Stand treatment for glioblastoma, including surgery followed by radiotherapy and chemotherapy (i.e., Temozolomide), has been largely unchanged since early 2000. Cancer immunotherapy has significantly shifted the paradigm of cancer management in the past decade with various degrees of success in treating many hematopoietic cancers and some solid tumors, such as melanoma and non-small cell lung cancer (NSCLC). However, little progress has been made in the field of neuro-oncology, especially in the application of immunotherapy to glioblastoma treatment. In this review, we attempted to summarize the common drug resistance mechanisms in glioblastoma from Temozolomide to immunotherapy. Our intent is not to repeat the well-known difficulty in the area of neuro-oncology, such as the blood-brain barrier, but to provide some fresh insights into the molecular mechanisms responsible for resistance by summarizing some of the most recent literature. Through this review, we also hope to share some new ideas for improving the immunotherapy outcome of glioblastoma treatment.

Keywords

Glioblastoma / immunotherapy / drug resistance / tumor microenvironment / immunosuppression

References

[1] Tran B.Survival comparison between glioblastoma multiforme and other incurable cancers.J Clin Neurosci2010;17:417-21

[2] Verhaak RG,Purdom E.Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.Cancer Cell2010;17:98-110

[3] Verdugo E,Medina MÁ.An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment.Cancer Commun2022;42:1083-111 PMCID:PMC9648390

[4] Wen PY,Lee EQ.Glioblastoma in adults: a society for neuro-oncology (SNO) and European society of neuro-oncology (EANO) consensus review on current management and future directions.Neuro Oncol2020;22:1073-113 PMCID:PMC7594557

[5] Drakulic D,Petrovic I.Current opportunities for targeting dysregulated neurodevelopmental signaling pathways in glioblastoma.Cells2022;11:2530 PMCID:PMC9406959

[6] Perez A.The evolving classification of diffuse gliomas: World Health Organization updates for 2021.Curr Neurol Neurosci Rep2021;21:67

[7] Grochans S,Simińska D.Epidemiology of glioblastoma multiforme-literature review.Cancers2022;14:2412 PMCID:PMC9139611

[8] Fisher JP.Current FDA-approved therapies for high-grade malignant gliomas.Biomedicines2021;9:324 PMCID:PMC8004675

[9] Xue J,Liu N.Ultrasound enhanced anti-tumor effect of temozolomide in glioblastoma cells and glioblastoma mouse model.Cell Mol Bioeng2019;12:99-106 PMCID:PMC6816674

[10] Barker CA,Chou JF.Radiotherapy and concomitant temozolomide may improve survival of elderly patients with glioblastoma.J Neurooncol2012;109:391-7 PMCID:PMC4712045

[11] Noch EK,Magge R.Challenges in the treatment of glioblastoma: multisystem mechanisms of therapeutic resistance.World Neurosurg2018;116:505-17

[12] Nicholas MK.Glioblastoma multiforme: evidence-based approach to therapy.Expert Rev Anticancer Ther2007;7:S23-7

[13] Whelan R,Knox AJS.Modulating the blood-brain barrier: a comprehensive review.Pharmaceutics2021;13:1980 PMCID:PMC8618722

[14] Kadry H,Cucullo L.A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity.Fluids Barriers CNS2020;17:69 PMCID:PMC7672931

[15] Hladky SB.Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood-brain barrier.Fluids Barriers CNS2018;15:30 PMCID:PMC6194691

[16] Zhao Z,Betsholtz C.Establishment and dysfunction of the blood-brain barrier.Cell2015;163:1064-78 PMCID:PMC4655822

[17] Simon MJ.Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.Biochim Biophys Acta2016;1862:442-51 PMCID:PMC4755861

[18] Wolburg H,Liebner S.Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse.Neurosci Lett2001;307:77-80

[19] Bhalerao A,Archie SR,Noorani B.In vitro modeling of the neurovascular unit: advances in the field.Fluids Barriers CNS2020;17:22 PMCID:PMC7077137

[20] Kane JR.The role of brain vasculature in glioblastoma.Mol Neurobiol2019;56:6645-53

[21] de Gooijer MC,Buil LCM.ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost.Cell Rep Med2021;2:100184 PMCID:PMC7817868

[22] Qosa H,Pasinelli P.Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders.Brain Res2015;1628:298-316 PMCID:PMC4681613

[23] Löscher W.Blood-brain barrier active efflux transporters: ATP-binding cassette gene family.NeuroRx2005;2:86-98 PMCID:PMC539326

[24] Liu H,Lu S.Solute carrier family of the organic anion-transporting polypeptides 1A2- Madin-Darby Canine Kidney II: a promising in vitro system to understand the role of organic anion-transporting polypeptide 1A2 in blood-brain barrier drug penetration.Drug Metab Dispos2015;43:1008-18

[25] He L,Nebert DW.Analysis and update of the human solute carrier (SLC) gene superfamily.Hum Genomics2009;3:195-206 PMCID:PMC2752037

[26] Hagenbuch B.Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family.Xenobiotica2008;38:778-801

[27] Thakkar N,Lee W.Role of organic anion-transporting polypeptides (OATPs) in cancer therapy.AAPS J2015;17:535-45 PMCID:PMC4406968

[28] Bronger H,Kopplow K.ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier.Cancer Res2005;65:11419-28

[29] Cooper E,Swanson MEV.Single-cell image analysis reveals over-expression of organic anion transporting polypeptides (OATPs) in human glioblastoma tissue.Neurooncol Adv2022;4:vdac166 PMCID:PMC9653174

[30] Zhang J,Bradshaw TD.Temozolomide: mechanisms of action, repair and resistance.Curr Mol Pharmacol2012;5:102-14

[31] Wu S,Gao F,Koul D.PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma.Neuro Oncol2021;23:920-31 PMCID:PMC8168825

[32] Lin K,Sundaram RK,Bindra RS.Mechanism-based design of agents that selectively target drug-resistant glioma.Science2022;377:502-11 PMCID:PMC9502022

[33] Tirrò E,Romano C.Prognostic and therapeutic roles of the insulin growth factor system in glioblastoma.Front Oncol2020;10:612385 PMCID:PMC7885861

[34] Lee SY.Temozolomide resistance in glioblastoma multiforme.Genes Dis2016;3:198-210 PMCID:PMC6150109

[35] Jimenez-Pascual A.Fibroblast growth factor receptor functions in glioblastoma.Cells2019;8:715 PMCID:PMC6678715

[36] Li X,Chen N.PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma.Oncotarget2016;7:33440-50 PMCID:PMC5078108

[37] Snuderl M,Le LP.Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.Cancer Cell2011;20:810-7

[38] Yin D,O’Kelly J.Connective tissue growth factor associated with oncogenic activities and drug resistance in glioblastoma multiforme.Int J Cancer2010;127:2257-67

[39] Nie E,Miao F.TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT.Neuro Oncol2021;23:435-46 PMCID:PMC7992894

[40] Huang T,Xu D.Stem cell programs in cancer initiation, progression, and therapy resistance.Theranostics2020;10:8721-43 PMCID:PMC7392012

[41] Mattei V,Martellucci S.The importance of tumor stem cells in glioblastoma resistance to therapy.Int J Mol Sci2021;22:3863 PMCID:PMC8068366

[42] Fidoamore A,Antonosante A.Glioblastoma stem cells microenvironment: the paracrine roles of the niche in drug and radioresistance.Stem Cells Int2016;2016:6809105 PMCID:PMC4736577

[43] Qin Y,Chen Y,Du S.Prognostic analysis of a hypoxia-associated lncRNA signature in glioblastoma and its pan-cancer landscape. J Neurol Surg A Cent Eur Neurosurg 2023.

[44] Ren P,Zeng ZR.A novel hypoxia-driven gene signature that can predict the prognosis and drug resistance of gliomas.Front Genet2022;13:976356 PMCID:PMC9478203

[45] Wu Y,Gu Z.Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.Nat Commun2020;11:6434 PMCID:PMC7749178

[46] Sturm D,Hovestadt V.Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.Cancer Cell2012;22:425-37

[47] Eyler CE,Hovestadt V,van Galen P.Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.Genome Biol2020;21:174 PMCID:PMC7364565

[48] Zhang S,Liang C.Long intergenic noncoding RNA 00021 promotes glioblastoma temozolomide resistance by epigenetically silencing p21 through Notch pathway.IUBMB Life2020;72:1747-56

[49] Bezecny P.Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience.Med Oncol2014;31:985

[50] Ramaiah MJ,Manyam RR.Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy.Life Sci2021;277:119504

[51] Carew JS,Nawrocki ST.Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy.Cancer Lett2008;269:7-17

[52] Zeng J,Sander M,Yan G.Oncolytic viro-immunotherapy: an emerging option in the treatment of gliomas.Front Immunol2021;12:721830 PMCID:PMC8524046

[53] Gaikwad S,Kaushik I,Srivastava SK.Immune checkpoint proteins: signaling mechanisms and molecular interactions in cancer immunotherapy.Semin Cancer Biol2022;86:137-50

[54] He X.Immune checkpoint signaling and cancer immunotherapy.Cell Res2020;30:660-9 PMCID:PMC7395714

[55] Vinay DS,Pawelec G.Immune evasion in cancer: mechanistic basis and therapeutic strategies.Semin Cancer Biol2015;35 Suppl:S185-98

[56] Reardon DA,Omuro A.Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the checkmate 143 phase 3 randomized clinical trial.JAMA Oncol2020;6:1003-10 PMCID:PMC7243167

[57] Omuro A,Sampson JH.Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: results from exploratory phase I cohorts of checkmate 143.Neurooncol Adv2022;4:vdac025 PMCID:PMC8989388

[58] Weller M,Idbaih A.CTIM-25. A randomized phase 3 study of nivolumab or placebo combined with radiotherapy plus temozolomide in patients with newly diagnosed glioblastoma with methylated mgmt promoter: checkmate 548.Neuro-Oncology2021;23:vi55-6 PMCID:PMC8598415

[59] Sampson JH,Preusser M.A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498.J Clin Oncol2016;34:TPS2079

[60] Medikonda R,Rahman M,Lim M.A review of glioblastoma immunotherapy.J Neurooncol2021;151:41-53

[61] Lin YJ,Lim M.CAR T cell therapy in primary brain tumors: current investigations and the future.Front Immunol2022;13:817296 PMCID:PMC8899093

[62] Maggs L,Dal AE,Ferrone S.CAR T cell-based immunotherapy for the treatment of glioblastoma.Front Neurosci2021;15:662064 PMCID:PMC8185049

[63] Brown CE,Starr R.Regression of glioblastoma after chimeric antigen receptor T-cell therapy.N Engl J Med2016;375:2561-9 PMCID:PMC5390684

[64] Majzner RG,Yeom KW.GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.Nature2022;603:934-41

[65] Siegler EL.Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: insights into mechanisms and novel therapies.Front Immunol2020;11:1973 PMCID:PMC7485001

[66] Schubert ML,Wang L.Side-effect management of chimeric antigen receptor (CAR) T-cell therapy.Ann Oncol2021;32:34-48

[67] Reardon DA,Tran DD.ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma.J Clin Oncol2015;33:2009

[68] Wen PY,Phuphanich S.A randomized, double-blind, placebo-controlled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients.J Clin Oncol2014;32:2005

[69] Liau LM,Tran DD.Correction to: first results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.J Transl Med2018;16:179

[70] Kaufman HL,Zloza A.Oncolytic viruses: a new class of immunotherapy drugs.Nat Rev Drug Discov2016;15:660 PMCID:PMC7608450

[71] Hemminki O,Hemminki A.Oncolytic viruses for cancer immunotherapy.J Hematol Oncol2020;13:84 PMCID:PMC7325106

[72] Engeland CE.Introduction to oncolytic virotherapy. In: Engeland CE, editor. Oncolytic Viruses. New York: Springer; 2020. p. 1-6.

[73] Filley AC.Immune system, friend or foe of oncolytic virotherapy?.Front Oncol2017;7:106 PMCID:PMC5440545

[74] Sugawara K,Ito H,Seto Y.Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation.Mol Ther Oncolytics2021;22:129-42 PMCID:PMC8413837

[75] Suryawanshi YR.Oncolytic viruses for malignant glioma: on the verge of success?.Viruses2021;13:1294 PMCID:PMC8310195

[76] Sha D,Budczies J,Stenzinger A.Tumor mutational burden as a predictive biomarker in solid tumors.Cancer Discov2020;10:1808-25 PMCID:PMC7710563

[77] Kao C,Datto MB.Tumor mutational burden (TMB) as a predictive biomarker of immune checkpoint blockade (ICB) in metastatic solid tumors.J Clin Oncol2020;38:80

[78] Leo A, Ugolini A, Veglia F. Myeloid cells in glioblastoma microenvironment.Cells2020;10:18 PMCID:PMC7824606

[79] Ravi VM,Will P.T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10.Nat Commun2022;13:925 PMCID:PMC8854421

[80] Andrews LP,Drake CG.LAG3 (CD223) as a cancer immunotherapy target.Immunol Rev2017;276:80-96 PMCID:PMC5338468

[81] Chongsathidkiet P,Koyama S.Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.Nat Med2018;24:1459-68 PMCID:PMC6129206

[82] Garris CS,Hla T.Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond.Immunology2014;142:347-53 PMCID:PMC4080950

[83] Sengupta S,Frishman C.Impact of temozolomide on immune response during malignant glioma chemotherapy.Clin Dev Immunol2012;2012:831090 PMCID:PMC3486128

[84] Mapelli R,Bianchi SP.Association between treatment-related lymphopenia and survival in glioblastoma patients following postoperative chemoradiotherapy.Strahlenther Onkol2022;198:448-57 PMCID:PMC9038819

[85] Lamano JB,Li YD.Glioblastoma-derived IL6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth.Clin Cancer Res2019;25:3643-57 PMCID:PMC6571046

[86] Wainwright DA,Chang AL.IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival.Clin Cancer Res2012;18:6110-21 PMCID:PMC3500434

[87] Xu L,Xu M,Yi L.Glioma-derived T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM4) contributes to tumor tolerance.J Biol Chem2011;286:36694-9 PMCID:PMC3196134

[88] Yekula A,Muralidharan K,Carter BS.Extracellular vesicles in glioblastoma tumor microenvironment.Front Immunol2019;10:3137 PMCID:PMC6990128

[89] Becker AP,Haque SJ.Tumor heterogeneity in glioblastomas: from light microscopy to molecular pathology.Cancers2021;13:761 PMCID:PMC7918815

[90] Darmanis S,Croote D.Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma.Cell Rep2017;21:1399-410 PMCID:PMC5810554

[91] Xie Y,Lugano R.Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing.JCI Insight2021;6:e150861 PMCID:PMC8410070

[92] Gularyan SK,Anufrieva KS.Investigation of inter- and intratumoral heterogeneity of glioblastoma using TOF-SIMS.Mol Cell Proteomics2020;19:960-70 PMCID:PMC7261812

[93] Patel AP,Trombetta JJ.Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.Science2014;344:1396-401 PMCID:PMC4123637

[94] Martínez A, Madurga R, García-Romero N, Ayuso-Sacido Á. Unravelling glioblastoma heterogeneity by means of single-cell RNA sequencing.Cancer Lett2022;527:66-79

[95] Zhang P,Liu L,Dong L.Current opinion on molecular characterization for GBM classification in guiding clinical diagnosis, prognosis, and therapy.Front Mol Biosci2020;7:562798 PMCID:PMC7506064

[96] Chen X,Zhao C.Molecular subtyping of glioblastoma based on immune-related genes for prognosis.Sci Rep2020;10:15495 PMCID:PMC7511296

[97] Neftel C,Filbin MG.An integrative model of cellular states, plasticity, and genetics for glioblastoma.Cell2019;178:835-49.e21 PMCID:PMC6703186

[98] Schaettler MO,Wang AZ.Characterization of the genomic and immunologic diversity of malignant brain tumors through multisector analysis.Cancer Discov2022;12:154-71 PMCID:PMC9296070

[99] Rosati E,Liaskou E,Karlsen TH.Overview of methodologies for T-cell receptor repertoire analysis.BMC Biotechnol2017;17:61 PMCID:PMC5504616

[100] Fu W,Li H.Single-cell atlas reveals complexity of the immunosuppressive microenvironment of initial and recurrent glioblastoma.Front Immunol2020;11:835 PMCID:PMC7221162

[101] Pinton L,Vettore M.The immune suppressive microenvironment of human gliomas depends on the accumulation of bone marrow-derived macrophages in the center of the lesion.J Immunother Cancer2019;7:58 PMCID:PMC6391795

[102] Coy S,Stopka SA.Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma.Nat Commun2022;13:4814

[103] Verkhratsky A.Biology of purinergic signalling: its ancient evolutionary roots, its omnipresence and its multiple functional significance.Bioessays2014;36:697-705

[104] Rodrigues JC,Zhang L.Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties.Neuro Oncol2010;12:351-65 PMCID:PMC2940603

[105] Jackson C,Phallen J,Lim M.Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment.Clin Dev Immunol2011;2011:732413 PMCID:PMC3235820

[106] Bloch O,Kaur R,Rutkowski MJ.Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages.Clin Cancer Res2013;19:3165-75 PMCID:PMC3742575

[107] Jacobs JF,Bol KF.Prognostic significance and mechanism of Treg infiltration in human brain tumors.J Neuroimmunol2010;225:195-9

[108] Chitadze G.Immune surveillance in glioblastoma: role of the NKG2D system and novel cell-based therapeutic approaches.Scand J Immunol2022;96:e13201

[109] Crane CA,Han SJ.Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy.Neuro Oncol2012;14:584-95 PMCID:PMC3337302

[110] Woroniecka K,Rhodin K.T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma.Clin Cancer Res2018;24:4175-86 PMCID:PMC6081269

[111] Mohme M.Tumor-specific T cell activation in malignant brain tumors.Front Immunol2020;11:205 PMCID:PMC7031483

[112] Liu S,Zhang C,Qiu X.T-cell exhaustion status under high and low levels of hypoxia-inducible factor 1α expression in glioma.Front Pharmacol2021;12:711772 PMCID:PMC8299942

[113] Sakaguchi S,Shimizu J.Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance.Immunol Rev2001;182:18-32

[114] Pacholczyk R,Kraj P.Origin and T cell receptor diversity of Foxp3⁺CD4⁺CD25⁺ T cells.Immunity2006;25:249-59

[115] Bilate AM.Induced CD4+Foxp3+ regulatory T cells in immune tolerance.Annu Rev Immunol2012;30:733-58

[116] Noyes D,Oseni S.Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells.J Immunother Cancer2022;10:e004605 PMCID:PMC9125763

[117] Amoozgar Z,Ren J.Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.Nat Commun2021;12:2582 PMCID:PMC8113440

[118] Yang F,Duan H.Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.Nat Commun2021;12:3424 PMCID:PMC8187342

[119] Domenis R,Toffoletto B.Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells.PLoS One2017;12:e0169932 PMCID:PMC5249124

[120] O’Rourke DM,Desai A.A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.Sci Transl Med2017;9:eaaa0984 PMCID:PMC5762203

[121] Zagzag D,Chiriboga L.Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain.Lab Invest2005;85:328-41

[122] Pistollato F,Rood BR.Hypoxia and HIF1α repress the differentiative effects of BMPs in high-grade glioma.Stem Cells2009;27:7-17

[123] Filatova A,Böğürcü N,Garvalov BK.Acidosis acts through HSP90 in a PHD/VHL-independent manner to promote HIF function and stem cell maintenance in glioma.Cancer Res2016;76:5845-56

[124] Murat A,Gorlia T.Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.J Clin Oncol2008;26:3015-24

[125] Goffart N,Lallemand F.CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone.Neuro Oncol2017;19:66-77 PMCID:PMC5193023

[126] Sesé B,Ensenyat-Mendez M.Glioblastoma embryonic-like stem cells exhibit immune-evasive phenotype.Cancer2022;14:2070 PMCID:PMC9104850

[127] Gaynor N,Collins DM.Immune checkpoint inhibitors: key trials and an emerging role in breast cancer.Semin Cancer Biol2022;79:44-57

[128] De Felice F,Palaia I.Immune check-point in cervical cancer.Crit Rev Oncol Hematol2018;129:40-3

[129] Zhao X,Wang Y.Targeting neoantigens for cancer immunotherapy.Biomark Res2021;9:61 PMCID:PMC8317330

[130] Schumacher TN.Neoantigens in cancer immunotherapy.Science2015;348:69-74

[131] Topalian SL,Anders RA.Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy.Nat Rev Cancer2016;16:275-87 PMCID:PMC5381938

[132] Alexandrov LB,Wedge DC.Signatures of mutational processes in human cancer.Nature2013;500:415-21 PMCID:PMC3776390

[133] Watowich MB,Larion M.T cell exhaustion in malignant gliomas.Trends Cancer2023;9:270-92 PMCID:PMC10038906

[134] Yue Q,Ye HX.The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma.J Neurooncol2014;116:251-9 PMCID:PMC3890045

[135] Tomaszewski WH,Chakraborty M.Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.Nat Commun2022;13:6483 PMCID:PMC9617949

[136] Mieczkowski J,Nauman P.Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.Oncotarget2015;6:33077-90 PMCID:PMC4741750

[137] Schartner JM,Van Handel M,Nadkarni N.Impaired capacity for upregulation of MHC class II in tumor-associated microglia.Glia2005;51:279-85

[138] Hussain SF,Suki D,Grimm E.The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses.Neuro Oncol2006;8:261-79 PMCID:PMC1871955

[139] Beauvillain C,Jarry U.Neonatal and adult microglia cross-present exogenous antigens.Glia2008;56:69-77

[140] Jarry U,Pineau L,Delneste Y.Efficiently stimulated adult microglia cross-prime naive CD8+ T cells injected in the brain.Eur J Immunol2013;43:1173-84

[141] Lee AH,Mochizuki AY.Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.Nat Commun2021;12:6938

[142] Chen AX,Zhao J.Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker.Genome Med2021;13:88 PMCID:PMC8136167

[143] Park JH,Lee HK.The immune landscape of high-grade brain tumor after treatment with immune checkpoint blockade.Front Immunol2022;13:1044544 PMCID:PMC9794569

[144] Simonds EF,Badillo O.Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma.J Immunother Cancer2021;9:e002181 PMCID:PMC8183210

[145] Iorgulescu JB,Speranza MC.Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma.Clin Cancer Res2021;27:276-87 PMCID:PMC8034990

[146] Shields LB,Shearer AJ.Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients.Radiat Oncol2015;10:222 PMCID:PMC4628380

[147] Ueda S,Nakahara Y,Shiraishi T.Induction of the DNA repair gene O6-methylguanine-DNA methyltransferase by dexamethasone in glioblastomas.J Neurosurg2004;101:659-63

[148] Aasland D,Tomicic MT,Kaina B.Repair gene O⁶ -methylguanine-DNA methyltransferase is controlled by SP1 and up-regulated by glucocorticoids, but not by temozolomide and radiation.J Neurochem2018;144:139-51

[149] Huarte M.The emerging role of lncRNAs in cancer.Nat Med2015;21:1253-61

[150] Zhang R,Lu WW,Zhu JS.LncRNAs and cancer.Oncol Lett2016;12:1233-9 PMCID:PMC4950797

[151] Schmitt AM.Long noncoding RNAs in cancer pathways.Cancer Cell2016;29:452-63 PMCID:PMC4831138

[152] Ghafouri-Fard S,Abak A.Role of long non-coding RNAs in conferring resistance in tumors of the nervous system.Front Oncol2021;11:670917 PMCID:PMC8219921

[153] Li Z,Zheng H.Modulating lncRNA SNHG15/CDK6/miR-627 circuit by palbociclib, overcomes temozolomide resistance and reduces M2-polarization of glioma associated microglia in glioblastoma multiforme.J Exp Clin Cancer Res2019;38:380 PMCID:PMC6714301

[154] Bonci D,Musumeci M.The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities.Nat Med2008;14:1271-7

[155] Ye X,Zhang Z.Identification of microRNAs associated with glioma diagnosis and prognosis.Oncotarget2017;8:26394-403 PMCID:PMC5432266

[156] Yang J,Deng Y.MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR.Int J Cancer2017;141:2082-92

[157] Hübner M,Effinger D.MicroRNA-93 acts as an “anti-inflammatory tumor suppressor” in glioblastoma.Neurooncol Adv2020;2:vdaa047 PMCID:PMC7282490

[158] Cloughesy TF,Orpilla JR.Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.Nat Med2019;25:477-86 PMCID:PMC6408961

[159] Wang EJ,Jain S.Immunotherapy resistance in glioblastoma.Front Genet2021;12:750675 PMCID:PMC8718605

[160] Goswami S,Cornish AE.Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma.Nat Med2020;26:39-46 PMCID:PMC7182038

[161] von Roemeling CA,Qie Y.Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity.Nat Commun2020;11:1508 PMCID:PMC7083893

[162] Mathewson ND,Tirosh I.Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis.Cell2021;184:1281-98.e26 PMCID:PMC7935772

[163] Di W,Wu F.Clinical characterization and immunosuppressive regulation of CD161 (KLRB1) in glioma through 916 samples.Cancer Sci2022;113:756-69 PMCID:PMC8819299

[164] Larson RC,Bailey SR.CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours.Nature2022;604:563-70

[165] Wang G,Zhong K.CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma.Mol Ther2023;31:134-53 PMCID:PMC9840126

[166] Amoozgar Z,Wang N.Combined blockade of VEGF, Angiopoietin-2, and PD1 reprograms glioblastoma endothelial cells into quasi-antigen-presenting cells. bioRxiv 2022.

[167] Bausart M,Malfanti A.Immunotherapy for glioblastoma: the promise of combination strategies.J Exp Clin Cancer Res2022;41:35 PMCID:PMC8787896

[168] Chen C,Chen Y.Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy.Sci Transl Med2022;14:eabn1128

[169] Klichinsky M,Shestova O.Human chimeric antigen receptor macrophages for cancer immunotherapy.Nat Biotechnol2020;38:947-53 PMCID:PMC7883632

[170] Zhang C,Jennewein L.ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma.J Natl Cancer Inst2016;108:djv375

[171] Ma R,Li Z.An oncolytic virus expressing IL15/IL15Rα combined with off-the-shelf EGFR-CAR NK cells targets glioblastoma.Cancer Res2021;81:3635-48 PMCID:PMC8562586

[172] Siemaszko J,Bogunia-Kubik K.NKG2D natural killer cell receptor-a short description and potential clinical applications.Cells2021;10:1420 PMCID:PMC8229527

[173] Zhang C,Scherer A.Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity.J Immunother Cancer2021;9:e002980 PMCID:PMC8488744

[174] Sun T,Luo J.Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males.J Clin Invest2014;124:4123-33 PMCID:PMC4151215

[175] Sun T,Ward S.An integrative view on sex differences in brain tumors.Cell Mol Life Sci2015;72:3323-42 PMCID:PMC4531141

[176] Ostrom QT,Wrensch MR.Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.Sci Rep2018;8:7352

[177] Zhang H,Zhang X.Sex difference of mutation clonality in diffuse glioma evolution.Neuro Oncol2019;21:201-13 PMCID:PMC6374767

[178] Shireman JM,Eickhoff JC.Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: a systematic review and meta-analysis.Neurooncol Adv2022;4:vdac082 PMCID:PMC9268746

[179] Bayik D,Park C.Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner.Cancer Discov2020;10:1210-25 PMCID:PMC7415660

[180] Sabbagh A,Ling X.Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models.Clin Cancer Res2021;27:4325-37 PMCID:PMC9012394

[181] Sheybani ND,Garrison WJ,Price RJ.Profiling of the immune landscape in murine glioblastoma following blood brain/tumor barrier disruption with MR image-guided focused ultrasound.J Neurooncol2022;156:109-22 PMCID:PMC8714701

[182] Hadjipanayis CG.5-ALA and FDA approval for glioma surgery.J Neurooncol2019;141:479-86 PMCID:PMC6445645

[183] Henderson BW.How does photodynamic therapy work?.Photochem Photobiol1992;55:145-57

[184] Zhang C,Vodovozova E.Photodynamic opening of the blood-brain barrier to high weight molecules and liposomes through an optical clearing skull window.Biomed Opt Express2018;9:4850-62 PMCID:PMC6179416

[185] Mroz P,Muchowicz A.Photodynamic therapy of murine mastocytoma induces specific immune responses against the cancer/testis antigen P1A.Cancer Res2013;73:6462-70 PMCID:PMC3831658

[186] Sasaki M,Kojima Y.Anti-tumor immunity enhancement by photodynamic therapy with talaporfin sodium and anti-programmed death 1 antibody.Mol Ther Oncolytics2023;28:118-31 PMCID:PMC9867957

[187] Semyachkina-glushkovskaya O,Fedosov I.A novel method to stimulate lymphatic clearance of beta-amyloid from mouse brain using noninvasive music-induced opening of the blood-brain barrier with EEG markers.Appl Sci2021;11:10287

[188] Semyachkina-Glushkovskaya O,Borisova E.Photodynamic opening of the blood-brain barrier and pathways of brain clearing.J Biophotonics2018;11:e201700287

[189] Tian T,Erel-Akbaba G.Immune checkpoint inhibition in GBM primed with radiation by engineered extracellular vesicles.ACS Nano2022;16:1940-53 PMCID:PMC9020451

[190] Sun T,Galstyan A.Blockade of a laminin-411-notch axis with CRISPR/Cas9 or a nanobioconjugate inhibits glioblastoma growth through tumor-microenvironment cross-talk.Cancer Res2019;79:1239-51 PMCID:PMC6625517

[191] Quader S,Toh K.Supramolecularly enabled pH- triggered drug action at tumor microenvironment potentiates nanomedicine efficacy against glioblastoma.Biomaterials2021;267:120463

[192] Fan R,Mu M.Engineering MMP-2 activated nanoparticles carrying B7-H3 bispecific antibodies for ferroptosis-enhanced glioblastoma immunotherapy.ACS Nano2023;17:9126-39

[193] Kannappan V,Wang Z.PLGA-nano-encapsulated disulfiram inhibits hypoxia-induced NF-κB, cancer stem cells, and targets glioblastoma in vitro and in vivo.Mol Cancer Ther2022;21:1273-84

[194] Zou Y,Yang Q.Blood-brain barrier-penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy.Sci Adv2022;8:eabm8011 PMCID:PMC9020780

[195] Jiang Y,Meng F.Apolipoprotein E peptide-directed chimeric polymersomes mediate an ultrahigh-efficiency targeted protein therapy for glioblastoma.ACS Nano2018;12:11070-9

[196] Okada M,Fujii SI.Identification of neoantigens in cancer cells as targets for immunotherapy.Int J Mol Sci2022;23:2594 PMCID:PMC8910406

[197] Lang F,Löwer M,Sahin U.Identification of neoantigens for individualized therapeutic cancer vaccines.Nat Rev Drug Discov2022;21:261-82