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Translational Therapeutics

Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them

Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood–brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.

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Fig. 1: Schematic representation of the molecules that favour the immunosuppressive tumour microenvironment in glioblastoma, and the immunotherapeutic drugs that have been investigated in clinical trials to enhance the anti-tumour response.

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References

  1. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro Oncol. 2020;22:iv1–96.

    PubMed  PubMed Central  Article  Google Scholar 

  2. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23:1231–51.

    CAS  PubMed  Article  Google Scholar 

  3. Goenka A, Tiek D, Song X, Huang T, Hu B, Cheng SY. The many facets of therapy resistance and tumor recurrence in glioblastoma. Cells. 2021;10:484.

  4. Oberheim Bush NA, Hervey-Jumper SL, Berger MS. Management of glioblastoma, present and future. World Neurosurg. 2019;131:328–38.

    PubMed  Article  Google Scholar 

  5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    CAS  PubMed  Article  Google Scholar 

  6. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.

    CAS  PubMed  Article  Google Scholar 

  7. Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017;376:1027–37.

    CAS  PubMed  Article  Google Scholar 

  8. Jackson CM, Choi J, Lim M. Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat Immunol. 2019;20:1100–9.

    CAS  PubMed  Article  Google Scholar 

  9. Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31:4085–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Mao H, Lebrun DG, Yang J, Zhu VF, Li M. Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest. 2012;30:48–56.

    PubMed  PubMed Central  Article  Google Scholar 

  11. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709–22.

    CAS  PubMed  Article  Google Scholar 

  13. Kunigelis KE, Vogelbaum MA. Therapeutic delivery to central nervous system. Neurosurg Clin N. Am. 2021;32:291–303.

    PubMed  Article  Google Scholar 

  14. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    CAS  PubMed  Article  Google Scholar 

  15. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases.1: bibliography. Am J Med Sci. 1893;105:487.

    Article  Google Scholar 

  16. Ehrlich P. Ueber den jetzigen Stand der Karzinomforschung. Beiträge zur experimentellen Pathologie und Chemotherapie. 1908. pp 117–64.

  17. Burnet FM. Immunological surveillance in neoplasia. Transpl Rev. 1971;7:3–25.

    CAS  Google Scholar 

  18. Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J. 1957;1:841–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Burnet M. Immunological factors in the process of carcinogenesis. Br Med Bull. 1964;20:154–8.

    CAS  PubMed  Article  Google Scholar 

  20. Thomas L, Lawrence H. Cellular and humoral aspects of the hypersensitive states. New York: Hoeber-Harper; 1959. pp. 529–32.

  21. Thomas L. On immunosurveillance in human cancer. Yale J Biol Med. 1982;55:329–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Old LJ, Boyse EA. Immunology of experimental tumors. Annu Rev Med. 1964;15:167–86.

    CAS  PubMed  Article  Google Scholar 

  23. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    CAS  PubMed  Article  Google Scholar 

  24. Amit L, Ben-Aharon I, Vidal L, Leibovici L, Stemmer S. The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors–a meta-analysis and systematic review. PLoS ONE. 2013;8:e51780.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Xu W, Gong Y, Kuang M, Wu P, Cao C, Chen J, et al. Survival benefit and safety of bevacizumab in combination with erlotinib as maintenance therapy in patients with metastatic colorectal cancer: a meta-analysis. Clin Drug Investig. 2017;37:155–65.

    CAS  PubMed  Article  Google Scholar 

  26. Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2021;151:41–53.

    PubMed  Article  Google Scholar 

  27. Chavez JC, Bachmeier C, Kharfan-Dabaja MA. CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Ther Adv Hematol. 2019;10:2040620719841581.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Leary A, Tan D, Ledermann J. Immune checkpoint inhibitors in ovarian cancer: where do we stand? Ther Adv Med Oncol. 2021;13:17588359211039899.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020;30:660–9.

    PubMed  PubMed Central  Article  Google Scholar 

  31. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212–8.

    CAS  PubMed  Article  Google Scholar 

  32. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, 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.

    CAS  PubMed  Article  Google Scholar 

  34. Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33:LBA109–LBA109.

    Article  Google Scholar 

  35. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6:8.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Zhang C, Durer S, Thandra KC, Kasi A. Chimeric antigen receptor T-cell therapy. In: StatPearls. FL: Treasure Island; 2021.

  38. Chuntova P, Chow F, Watchmaker PB, Galvez M, Heimberger AB, Newell EW, et al. Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank. Neuro Oncol. 2021;23:356–75.

    CAS  PubMed  Article  Google Scholar 

  39. Fisher JP, Adamson DC. Current FDA-approved therapies for high-grade malignant gliomas. Biomedicines. 2021;9:324.

  40. Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1003–10.

    PubMed  Article  Google Scholar 

  41. Murphy JB, Sturm E. Conditions determining the transplantability of tissues in the brain. J Exp Med. 1923;38:183–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Ehrlich P. Das sauerstufbudurfnis des organismus. In: Eine Farbenanalytische Studie. Berlin: Hirschwald; 1885.

  43. Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29:58–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212:991–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Sampson JH, Gunn MD, Fecci PE, Ashley DM. Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer. 2020;20:12–25.

    CAS  PubMed  Article  Google Scholar 

  47. Larsen JM, Martin DR, Byrne ME. Recent advances in delivery through the blood-brain barrier. Curr Top Med Chem. 2014;14:1148–60.

    CAS  PubMed  Article  Google Scholar 

  48. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7:a020412.

    PubMed  PubMed Central  Article  Google Scholar 

  49. Jones KA, Maltby S, Plank MW, Kluge M, Nilsson M, Foster PS, et al. Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke. Brain Behav Immun. 2018;67:299–307.

    CAS  PubMed  Article  Google Scholar 

  50. Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharm. 2009;4:462–75.

    Article  Google Scholar 

  51. Lossinsky AS, Shivers RR. Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. Histol Histopathol. 2004;19:535–64.

    CAS  PubMed  Google Scholar 

  52. Watkins S, Robel S, Kimbrough IF, Robert SM, Ellis-Davies G, Sontheimer H. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun. 2014;5:4196.

    CAS  PubMed  Article  Google Scholar 

  53. Vajkoczy P, Menger MD. Vascular microenvironment in gliomas. Cancer Treat Res. 2004;117:249–62.

    CAS  PubMed  Article  Google Scholar 

  54. O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. 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 Med. 2017;9:eaaa0984.

  55. Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Abid H, Watthanasuntorn K, Shah O, Gnanajothy R. Efficacy of pembrolizumab and nivolumab in crossing the blood brain barrier. Cureus. 2019;11:e4446.

    PubMed  PubMed Central  Google Scholar 

  57. Portnow J, Wang D, Blanchard MS, Tran V, Alizadeh D, Starr R, et al. Systemic anti-PD-1 immunotherapy results in PD-1 blockade on T cells in the cerebrospinal fluid. JAMA Oncol. 2020; https://doi.org/10.1001/jamaoncol.2020.4508.

  58. Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018;20:184–91.

    CAS  PubMed  Article  Google Scholar 

  59. Arvanitis CD, Ferraro GB, Jain RK. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20:26–41.

    CAS  PubMed  Article  Google Scholar 

  60. Pitz MW, Desai A, Grossman SA, Blakeley JO. Tissue concentration of systemically administered antineoplastic agents in human brain tumors. J Neurooncol. 2011;104:629–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Westphal M, Yla-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, et al. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:823–33.

    CAS  PubMed  Article  Google Scholar 

  62. Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, Markert JM. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther. 2014;22:1056–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–74.

    CAS  PubMed  Article  Google Scholar 

  64. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA. 2000;97:12846–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Fares J, Ahmed AU, Ulasov IV, Sonabend AM, Miska J, Lee-Chang C, et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 2021;22:1103–14.

    CAS  PubMed  Article  Google Scholar 

  66. D'Amico RS, Aghi MK, Vogelbaum MA, Bruce JN. Convection-enhanced drug delivery for glioblastoma: a review. J Neurooncol. 2021;151:415–27.

    PubMed  PubMed Central  Article  Google Scholar 

  67. Peschillo S, Caporlingua A, Diana F, Caporlingua F, Delfini R. New therapeutic strategies regarding endovascular treatment of glioblastoma, the role of the blood-brain barrier and new ways to bypass it. J Neurointerv Surg. 2016;8:1078–82.

    CAS  PubMed  Article  Google Scholar 

  68. Hsu JF, Chu SM, Liao CC, Wang CJ, Wang YS, Lai MY, et al. Nanotechnology and nanocarrier-based drug delivery as the potential therapeutic strategy for glioblastoma multiforme: an update. Cancers. 2021;13:195.

  69. Idbaih A, Ducray F, Stupp R, Baize N, Chinot OL, Groot JFD, et al. A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin. J Clin Oncol. 2021;39:2049–2049.

    Article  Google Scholar 

  70. Sabbagh A, Beccaria K, Ling X, Marisetty A, Ott M, Caruso H, et al. Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models. Clin Cancer Res. 2021; https://doi.org/10.1158/1078-0432.CCR-20-3760.

  71. Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016;8:343re342.

    Article  CAS  Google Scholar 

  72. Institute NC. The Cancer Genome Atlas Program. https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga Accessed 05/28.

  73. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32:42–56 e46.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Khalafallah AM, Huq S, Jimenez AE, Serra R, Bettegowda C, Mukherjee D. "Zooming in" on glioblastoma: understanding tumor heterogeneity and its clinical implications in the era of single-cell ribonucleic acid sequencing. Neurosurgery. 2021;88:477–86.

    PubMed  Article  Google Scholar 

  77. Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA. 2013;110:4009–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Qazi MA, Vora P, Venugopal C, Sidhu SS, Moffat J, Swanton C, et al. Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Ann Oncol. 2017;28:1448–56.

    CAS  PubMed  Article  Google Scholar 

  79. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature. 2013;501:355–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Lee JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, et al. Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet. 2017;49:594–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Reinartz R, Wang S, Kebir S, Silver DJ, Wieland A, Zheng T, et al. Functional subclone profiling for prediction of treatment-induced intratumor population shifts and discovery of rational drug combinations in human glioblastoma. Clin Cancer Res. 2017;23:562–74.

    CAS  PubMed  Article  Google Scholar 

  82. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343:189–93.

    CAS  PubMed  Article  Google Scholar 

  83. Kim H, Zheng S, Amini SS, Virk SM, Mikkelsen T, Brat DJ, et al. Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution. Genome Res. 2015;25:316–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Kim J, Lee IH, Cho HJ, Park CK, Jung YS, Kim Y, et al. Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell. 2015;28:318–28.

    CAS  PubMed  Article  Google Scholar 

  85. Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell. 2017;31:326–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Montoya ML, Kasahara N, Okada H. Introduction to immunotherapy for brain tumor patients: challenges and future perspectives. Neurooncol Pr. 2020;7:465–76.

    Google Scholar 

  87. Muller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, 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;18:234.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF, et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 2016;17:2445–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Ginhoux F, Schultze JL, Murray PJ, Ochando J, Biswas SK. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol. 2016;17:34–40.

    CAS  PubMed  Article  Google Scholar 

  90. Gabrusiewicz K, Rodriguez B, Wei J, Hashimoto Y, Healy LM, Maiti SN, et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight. 2016;1:1–19.

    Article  Google Scholar 

  91. Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17:428–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Piperi C, Papavassiliou KA, Papavassiliou AG. Pivotal role of STAT3 in shaping glioblastoma immune microenvironment. Cells. 2019;8:1398.

  93. Ott M, Kassab C, Marisetty A, Hashimoto Y, Wei J, Zamler D, et al. Radiation with STAT3 blockade triggers dendritic cell-T cell interactions in the glioma microenvironment and therapeutic efficacy. Clin Cancer Res. 2020;26:4983–94.

    CAS  PubMed  Article  Google Scholar 

  94. Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B. Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009;57:1458–67.

    PubMed  Article  Google Scholar 

  95. Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67:9630–6.

    CAS  PubMed  Article  Google Scholar 

  96. Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med. 2012;18:519–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Almahariq MF, Quinn TJ, Kesarwani P, Kant S, Miller CR, Chinnaiyan P. Inhibition of colony-stimulating factor-1 receptor enhances the efficacy of radiotherapy and reduces immune suppression in glioblastoma. Vivo. 2021;35:119–29.

    CAS  Article  Google Scholar 

  99. Wei J, Chen P, Gupta P, Ott M, Zamler D, Kassab C, et al. Immune biology of glioma-associated macrophages and microglia: functional and therapeutic implications. Neuro Oncol. 2020;22:180–94.

    CAS  PubMed  Article  Google Scholar 

  100. Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci. 2019;22:729–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest. 2017;127:1425–37.

    PubMed  PubMed Central  Article  Google Scholar 

  102. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22:586–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Goswami S, Walle T, Cornish AE, Basu S, Anandhan S, Fernandez I, et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat Med. 2020;26:39–46.

    CAS  PubMed  Article  Google Scholar 

  104. Zhang B. CD73: a novel target for cancer immunotherapy. Cancer Res. 2010;70:6407–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Kazemi MH, Raoofi Mohseni S, Hojjat-Farsangi M, Anvari E, Ghalamfarsa G, Mohammadi H, et al. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J Cell Physiol. 2018;233:2032–57.

    CAS  PubMed  Article  Google Scholar 

  106. Ohta A, Sitkovsky M. Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol. 2014;5:304.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Azambuja JH, Schuh RS, Michels LR, Iser IC, Beckenkamp LR, Roliano GG, et al. Blockade of CD73 delays glioblastoma growth by modulating the immune environment. Cancer Immunol Immunother. 2020;69:1801–12.

    CAS  PubMed  Article  Google Scholar 

  108. Frederico SC, Hancock JC, Brettschneider EES, Ratnam NM, Gilbert MR, Terabe M. Making a cold tumor hot: the role of vaccines in the treatment of glioblastoma. Front Oncol. 2021;11:672508.

    PubMed  PubMed Central  Article  Google Scholar 

  109. Grabowski MM, Sankey EW, Ryan KJ, Chongsathidkiet P, Lorrey SJ, Wilkinson DS, et al. Immune suppression in gliomas. J Neurooncol. 2021;151:3–12.

    PubMed  Article  Google Scholar 

  110. Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE. T-cell dysfunction in glioblastoma: applying a new framework. Clin Cancer Res. 2018;24:3792–802.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Rosato PC, Wijeyesinghe S, Stolley JM, Nelson CE, Davis RL, Manlove LS, et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat Commun. 2019;10:567.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002;62:3347–50.

    CAS  PubMed  Google Scholar 

  113. Dziurzynski K, Chang SM, Heimberger AB, Kalejta RF, McGregor Dallas SR, Smit M, et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012;14:246–55.

    PubMed  PubMed Central  Article  Google Scholar 

  114. Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, McLendon RE, et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 2008;10:10–18.

    PubMed  PubMed Central  Article  Google Scholar 

  115. Weathers SP, Penas-Prado M, Pei BL, Ling X, Kassab C, Banerjee P, et al. Glioblastoma-mediated Immune dysfunction limits CMV-specific T cells and therapeutic responses: results from a phase I/II trial. Clin Cancer Res. 2020;26:3565–77.

    CAS  PubMed  Article  Google Scholar 

  116. Batich KA, Mitchell DA, Healy P, Herndon JE 2nd, Sampson JH. Once, twice, three times a finding: reproducibility of dendritic cell vaccine trials targeting cytomegalovirus in glioblastoma. Clin Cancer Res. 2020;26:5297–303.

    CAS  PubMed  Article  Google Scholar 

  117. Reap EA, Suryadevara CM, Batich KA, Sanchez-Perez L, Archer GE, Schmittling RJ, et al. Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma. Cancer Res. 2018;78:256–64.

    CAS  PubMed  Article  Google Scholar 

  118. Mitchell DA, Batich KA, Gunn MD, Huang MN, Sanchez-Perez L, Nair SK, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519:366–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722–9.

    PubMed  PubMed Central  Article  Google Scholar 

  120. Rahman M, Sawyer WG, Lindhorst S, Deleyrolle LP, Harrison JK, Karachi A, et al. Adult immuno-oncology: using past failures to inform the future. Neuro Oncol. 2020;22:1249–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305–34.

    CAS  PubMed  Article  Google Scholar 

  122. Fields P, Fitch FW, Gajewski TF. Control of T lymphocyte signal transduction through clonal anergy. J Mol Med. 1996;74:673–83.

    CAS  PubMed  Article  Google Scholar 

  123. Kang SM, Beverly B, Tran AC, Brorson K, Schwartz RH, Lenardo MJ. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992;257:1134–8.

    CAS  PubMed  Article  Google Scholar 

  124. Liu F, Huang J, Liu X, Cheng Q, Luo C, Liu Z. CTLA-4 correlates with immune and clinical characteristics of glioma. Cancer Cell Int. 2020;20:7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, Nakashima H, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv. 2018;4:eaar2766.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity. Nat Immunol. 2017;18:716–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996;274:1363–6.

    CAS  PubMed  Article  Google Scholar 

  128. Saas P, Walker PR, Hahne M, Quiquerez AL, Schnuriger V, Perrin G, et al. Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest. 1997;99:1173–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Frankel B, Longo SL, Ryken TC. Human astrocytomas co-expressing Fas and Fas ligand also produce TGFbeta2 and Bcl-2. J Neurooncol. 1999;44:205–12.

    CAS  PubMed  Article  Google Scholar 

  130. Didenko VV, Ngo HN, Minchew C, Baskin DS. Apoptosis of T lymphocytes invading glioblastomas multiforme: a possible tumor defense mechanism. J Neurosurg. 2002;96:580–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Walker DG, Chuah T, Rist MJ, Pender MP. T-cell apoptosis in human glioblastoma multiforme: implications for immunotherapy. J Neuroimmunol. 2006;175:59–68.

    CAS  PubMed  Article  Google Scholar 

  132. El Andaloussi A, Lesniak MS. An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. Neuro Oncol. 2006;8:234–43.

    PubMed  Article  Google Scholar 

  133. Tamura R, Ohara K, Sasaki H, Morimoto Y, Kosugi K, Yoshida K, et al. Difference in immunosuppressive cells between peritumoral area and tumor core in glioblastoma. World Neurosurg. 2018;120:e601–e610.

    PubMed  Article  Google Scholar 

  134. DiDomenico J, Lamano JB, Oyon D, Li Y, Veliceasa D, Kaur G, et al. The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma. Oncoimmunology. 2018;7:e1448329.

    PubMed  PubMed Central  Article  Google Scholar 

  135. Ding XC, Wang LL, Zhang XD, Xu JL, Li PF, Liang H, et al. The relationship between expression of PD-L1 and HIF-1alpha in glioma cells under hypoxia. J Hematol Oncol. 2021;14:92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66:3294–302.

    CAS  PubMed  Article  Google Scholar 

  137. Li J, He Y, Hao J, Ni L, Dong C. High levels of eomes promote exhaustion of anti-tumor CD8(+) T cells. Front Immunol. 2018;9:2981.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Weulersse M, Asrir A, Pichler AC, Lemaitre L, Braun M, Carrie N, et al. Eomes-dependent loss of the co-activating receptor CD226 Restrains CD8(+) T cell anti-tumor functions and limits the efficacy of cancer immunotherapy. Immunity. 2020;53:824–39. e810

    CAS  PubMed  Article  Google Scholar 

  139. Sun R, Wu Y, Zhou H, Wu Y, Yang Z, Gu Y, et al. Eomes impedes durable response to tumor immunotherapy by inhibiting stemness, tissue residency, and promoting the dysfunctional state of intratumoral CD8(+) T cells. Front Cell Dev Biol. 2021;9:640224.

    PubMed  PubMed Central  Article  Google Scholar 

  140. Woroniecka K, Chongsathidkiet P, Rhodin K, Kemeny H, Dechant C, Farber SH, et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin Cancer Res. 2018;24:4175–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Ott M, Prins RM, Heimberger AB. The immune landscape of common CNS malignancies: implications for immunotherapy. Nat Rev Clin Oncol. 2021;18:729–44.

    PubMed  Article  Google Scholar 

  143. Ott M, Tomaszowski KH, Marisetty A, Kong LY, Wei J, Duna M, et al. Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration. JCI Insight. 2020;5:1–17.

    Article  Google Scholar 

  144. Collins K, Mitchell JR. Telomerase in the human organism. Oncogene. 2002;21:564–79.

    CAS  PubMed  Article  Google Scholar 

  145. Pierini T, Nardelli C, Lema Fernandez AG, Pierini V, Pellanera F, Nofrini V, et al. New somatic TERT promoter variants enhance the telomerase activity in glioblastoma. Acta Neuropathol Commun. 2020;8:145.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA. 2013;110:6021–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Huff WX, Bam M, Shireman JM, Kwon JH, Song L, Newman S, et al. Aging- and tumor-mediated increase in CD8(+)CD28(-) T cells might impose a strong barrier to success of immunotherapy in glioblastoma. Immunohorizons. 2021;5:395–409.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158–69.

    CAS  PubMed  Article  Google Scholar 

  149. Focosi D, Bestagno M, Burrone O, Petrini M. CD57+ T lymphocytes and functional immune deficiency. J Leukoc Biol. 2010;87:107–16.

    CAS  PubMed  Article  Google Scholar 

  150. Fornara O, Odeberg J, Wolmer Solberg N, Tammik C, Skarman P, Peredo I, et al. Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery. Oncoimmunology. 2015;4:e1036211.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Lee-Chang C, Miska J, Hou D, Rashidi A, Zhang P, Burga RA, et al. Activation of 4-1BBL+ B cells with CD40 agonism and IFNgamma elicits potent immunity against glioblastoma. J Exp Med. 2021;218:1–23.

    Article  CAS  Google Scholar 

  152. Ashley DM, Faiola B, Nair S, Hale LP, Bigner DD, Gilboa E. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. J Exp Med. 1997;186:1177–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Schaller TH, Sampson JH. Advances and challenges: dendritic cell vaccination strategies for glioblastoma. Expert Rev Vaccines. 2017;16:27–36.

    CAS  PubMed  Article  Google Scholar 

  154. Lee-Chang C, Rashidi A, Miska J, Zhang P, Pituch KC, Hou D, et al. Myeloid-derived suppressive cells promote B cell-mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer Immunol Res. 2019;7:1928–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med. 2018;24:1459–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. Brooks WH, Netsky MG, Normansell DE, Horwitz DA. Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J Exp Med. 1972;136:1631–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Roszman T, Elliott L, Brooks W. Modulation of T-cell function by gliomas. Immunol Today. 1991;12:370–4.

    CAS  PubMed  Article  Google Scholar 

  158. Malek TR. The biology of interleukin-2. Annu Rev Immunol. 2008;26:453–79.

    CAS  PubMed  Article  Google Scholar 

  159. Elliott LH, Brooks WH, Roszman TL. Cytokinetic basis for the impaired activation of lymphocytes from patients with primary intracranial tumors. J Immunol. 1984;132:1208–15.

    CAS  PubMed  Google Scholar 

  160. Elliott LH, Brooks WH, Roszman TL. Inability of mitogen-activated lymphocytes obtained from patients with malignant primary intracranial tumors to express high affinity interleukin 2 receptors. J Clin Invest. 1990;86:80–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Singer A, Adoro S, Park JH. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol. 2008;8:788–801.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Ayasoufi K, Pfaller CK, Evgin L, Khadka RH, Tritz ZP, Goddery EN, et al. Brain cancer induces systemic immunosuppression through release of non-steroid soluble mediators. Brain. 2020;143:3629–52.

    PubMed  PubMed Central  Article  Google Scholar 

  163. Allende ML, Dreier JL, Mandala S, Proia RL. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J Biol Chem. 2004;279:15396–401.

    CAS  PubMed  Article  Google Scholar 

  164. Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, et al. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009;23:1541–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Domenis R, Cesselli D, Toffoletto B, Bourkoula E, Caponnetto F, Manini I, et al. Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells. PLoS ONE. 2017;12:e0169932.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. Gabrusiewicz K, Li X, Wei J, Hashimoto Y, Marisetty AL, Ott M, et al. Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes. Oncoimmunology. 2018;7:e1412909.

    PubMed  PubMed Central  Article  Google Scholar 

  167. Harshyne LA, Nasca BJ, Kenyon LC, Andrews DW, Hooper DC. Serum exosomes and cytokines promote a T-helper cell type 2 environment in the peripheral blood of glioblastoma patients. Neuro Oncol. 2016;18:206–15.

    CAS  PubMed  Article  Google Scholar 

  168. Kostaras X, Cusano F, Kline GA, Roa W, Easaw J. Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol. 2014;21:e493–503.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Roth P, Happold C, Weller M. Corticosteroid use in neuro-oncology: an update. Neurooncol Pr. 2015;2:6–12.

    Google Scholar 

  170. Dubinski D, Hattingen E, Senft C, Seifert V, Peters KG, Reiss Y, et al. Controversial roles for dexamethasone in glioblastoma—opportunities for novel vascular targeting therapies. J Cereb Blood Flow Metab. 2019;39:1460–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Shields LB, Shelton BJ, Shearer AJ, Chen L, Sun DA, Parsons S, et al. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol. 2015;10:222.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol. 2018;36:2872–8.

    CAS  PubMed  Article  Google Scholar 

  173. Upadhyayula PS, Higgins DM, Argenziano MG, Spinazzi EF, Wu CC, Canoll P, et al. The sledgehammer in precision medicine: dexamethasone and immunotherapeutic treatment of glioma. Cancer Investig. 2021;1–18; https://doi.org/10.1080/07357907.2021.1944178.

  174. Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, et al. Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clin Cancer Res. 2021;27:276–87.

    CAS  PubMed  Article  Google Scholar 

  175. Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565:234–9.

    CAS  PubMed  Article  Google Scholar 

  176. Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, et al. Selective inhibition of low-affinity memory CD8(+) T cells by corticosteroids. J Exp Med. 2019;216:2701–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. Badie B, Schartner JM, Paul J, Bartley BA, Vorpahl J, Preston JK. Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study. J Neurosurg. 2000;93:634–9.

    CAS  PubMed  Article  Google Scholar 

  178. Vredenburgh JJ, Cloughesy T, Samant M, Prados M, Wen PY, Mikkelsen T, et al. Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study. Oncologist. 2010;15:1329–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14:1131–8.

    CAS  PubMed  Article  Google Scholar 

  180. de Groot J, Liang J, Kong LY, Wei J, Piao Y, Fuller G, et al. Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma. Oncotarget. 2012;3:1036–48.

    PubMed  PubMed Central  Article  Google Scholar 

  181. Arevalo OD, Soto C, Rabiei P, Kamali A, Ballester LY, Esquenazi Y, et al. Assessment of glioblastoma response in the era of bevacizumab: longstanding and emergent challenges in the imaging evaluation of pseudoresponse. Front Neurol. 2019;10:460.

    PubMed  PubMed Central  Article  Google Scholar 

  182. Lucio-Eterovic AK, Piao Y, de Groot JF. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res. 2009;15:4589–99.

    CAS  PubMed  Article  Google Scholar 

  183. Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, et al. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia. 2000;2:306–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Lake RA, Robinson BW. Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer. 2005;5:397–405.

    CAS  PubMed  Article  Google Scholar 

  185. Pagani E, Pepponi R, Fuggetta MP, Prete SP, Turriziani M, Bonmassar L, et al. DNA repair enzymes and cytotoxic effects of temozolomide: comparative studies between tumor cells and normal cells of the immune system. J Chemother. 2003;15:173–83.

    CAS  PubMed  Article  Google Scholar 

  186. Saha D, Rabkin SD, Martuza RL. Temozolomide antagonizes oncolytic immunovirotherapy in glioblastoma. J Immunother Cancer. 2020;8:1–8.

    CAS  Article  Google Scholar 

  187. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13:324–33.

    CAS  PubMed  Article  Google Scholar 

  188. Mathios D, Kim JE, Mangraviti A, Phallen J, Park CK, Jackson CM, et al. Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci Transl Med. 2016;8:370ra180.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. Sahebjam S, Sharabi A, Lim M, Kesarwani P, Chinnaiyan P. Immunotherapy and radiation in glioblastoma. J Neurooncol. 2017;134:531–9.

    CAS  PubMed  Article  Google Scholar 

  190. Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget. 2014;5:403–16.

    PubMed  Article  Google Scholar 

  191. Liao Y, Liu S, Fu S, Wu J. HMGB1 in radiotherapy: a two headed signal regulating tumor radiosensitivity and immunity. Onco Targets Ther. 2020;13:6859–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. Arrieta VA, Chen AX, Kane JR, Kang SJ, Kassab C, Dmello C, et al. ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma. Nat Cancer. 2021;2:1372–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. McGrail DJ, Pilie PG, Rashid NU, Voorwerk L, Slagter M, Kok M, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 2021;32:661–72.

    CAS  PubMed  Article  Google Scholar 

  195. McGrail DJ, Pilie PG, Dai H, Lam TNA, Liang Y, Voorwerk L, et al. Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers. Sci Transl Med. 2021;13:eabe6201.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. Friendlander AH, Ettinger RL. Karnofsky performance status scale. Spec Care Dent. 2009;29:147–8.

    Article  Google Scholar 

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MJM and KJH contributed to the conceptualisation and outline. The first draft of the manuscript was written by KJH and corrected by MJM, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. RM contributed to the figure preparation.

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Habashy, K.J., Mansour, R., Moussalem, C. et al. Challenges in glioblastoma immunotherapy: mechanisms of resistance and therapeutic approaches to overcome them. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-01864-w

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