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Targeting oncometabolism to maximize immunotherapy in malignant brain tumors

Oncogene volume 41, pages 2663–2671 (2022)Cite this article

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Abstract

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed “tumor immunometabolism”. Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

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Fig. 1: Metabolic interaction(s) between glioma cells, T cells, and myeloid-derived suppressor cells (MDSCs).
Fig. 2: Targeting tumor metabolism in gliomas with biologics and small-molecule inhibitors.

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References

  1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21:v1–100.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rogers TW, Toor G, Drummond K, Love C, Field K, Asher R, et al. The 2016 revision of the WHO Classification of Central Nervous System Tumours: retrospective application to a cohort of diffuse gliomas. J Neurooncol. 2018;137:181–9.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol. 2011;13:317–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mooney J, Bernstock JD, Ilyas A, Ibrahim A, Yamashita D, Markert JM, et al. Current approaches and challenges in the molecular therapeutic targeting of glioblastoma. World Neurosurg. 2019;129:90–100.

    Article  PubMed  Google Scholar 

  7. Galluzzi L, Kroemer G. Preface: oncometabolism: a new field of research with profound therapeutic implications. Methods Enzymol. 2014;542:xix–xxiii.

    Article  PubMed  Google Scholar 

  8. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2010;465:966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sciacovelli M, Frezza C. Fumarate drives EMT in renal cancer. Cell Death Differ. 2017;24:1–2.

    Article  CAS  PubMed  Google Scholar 

  10. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Disco. 2013;12:829–46.

    Article  CAS  Google Scholar 

  11. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kareva I, Hahnfeldt P. The emerging “hallmarks” of metabolic reprogramming and immune evasion: distinct or linked? Cancer Res. 2013;73:2737–42.

    Article  CAS  PubMed  Google Scholar 

  13. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hill BG, Shiva S, Ballinger S, Zhang J, Darley-Usmar VM. Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine. Biol Chem. 2019;401:3–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 2013;19:901–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kathagen-Buhmann A, Schulte A, Weller J, Holz M, Herold-Mende C, Glass R, et al. Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation. Neuro Oncol. 2016;18:1219–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, et al. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro Oncol. 2017;19:43–54.

    Article  PubMed  CAS  Google Scholar 

  18. Libby CJ, Tran AN, Scott SE, Griguer C, Hjelmeland AB. The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells. Biochim Biophys Acta Rev Cancer. 2018;1869:175–88. https://doi.org/10.1016/j.bbcan.2018.01.004.

  19. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89.

  20. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–77.

    Article  CAS  PubMed  Google Scholar 

  22. Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27:977–87 e974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Reinfeld BI, Madden MZ, Wolf MM, Chytil A, Bader JE, Patterson AR, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021;593:282–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou W, Wahl DR. Metabolic abnormalities in glioblastoma and metabolic strategies to overcome treatment resistance. Cancers. 2019;11:1231. https://doi.org/10.3390/cancers11091231.

  26. Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci. 2013;16:1373–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20:61–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Libby CJ, Zhang S, Benavides GA, Scott SE, Li Y, Redmann M, et al. Identification of compounds that decrease glioblastoma growth and glucose uptake in vitro. ACS Chem Biol. 2018;13:2048–57.

    Article  CAS  PubMed Central  Google Scholar 

  29. Kuang R, Jahangiri A, Mascharak S, Nguyen A, Chandra A, Flanigan PM, et al. GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance. JCI Insight. 2017;2:e88815.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cosset E, Ilmjarv S, Dutoit V, Elliott K, von Schalscha T, Camargo MF, et al. Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma. Cancer Cell. 2017;32:856–68 e855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sanzey M, Abdul Rahim SA, Oudin A, Dirkse A, Kaoma T, Vallar L, et al. Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. PLoS ONE. 2015;10:e0123544.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Mehta MM, Weinberg SE, Steinert EM, Chhiba K, Martinez CA, Gao P, et al. Hexokinase 2 is dispensable for T cell-dependent immunity. Cancer Metab. 2018;6:10.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wicks RT, Azadi J, Mangraviti A, Zhang I, Hwang L, Joshi A, et al. Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma. Neuro Oncol. 2015;17:70–80.

    Article  CAS  PubMed  Google Scholar 

  34. Le Calve B, Rynkowski M, Le Mercier M, Bruyere C, Lonez C, Gras T, et al. Long-term in vitro treatment of human glioblastoma cells with temozolomide increases resistance in vivo through up-regulation of GLUT transporter and aldo-keto reductase enzyme AKR1C expression. Neoplasia. 2010;12:727–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Velpula KK, Guda MR, Sahu K, Tuszynski J, Asuthkar S, Bach SE, et al. Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma. Oncotarget. 2017;8:35639–55.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yuen CA, Asuthkar S, Guda MR, Tsung AJ, Velpula KK. Cancer stem cell molecular reprogramming of the Warburg effect in glioblastomas: a new target gleaned from an old concept. CNS Oncol. 2016;5:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2:31ra34.

    Article  CAS  PubMed  Google Scholar 

  38. Shen H, Hau E, Joshi S, Dilda PJ, McDonald KL. Sensitization of glioblastoma cells to irradiation by modulating the glucose metabolism. Mol Cancer Ther. 2015;14:1794–804.

    Article  CAS  PubMed  Google Scholar 

  39. Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol. 2021;21:151–61.

    Article  CAS  PubMed  Google Scholar 

  40. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L, et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci USA. 2014;111:12823–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24:657–71.

    Article  CAS  PubMed  Google Scholar 

  43. Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25:1282–93 e1287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature. 2021;591:652–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell. 2020;77:213–27 e215.

    Article  CAS  PubMed  Google Scholar 

  46. Krzak G, Willis CM, Smith JA, Pluchino S, Peruzzotti-Jametti L. Succinate receptor 1: an emerging regulator of myeloid cell function in inflammation. Trends Immunol. 2021;42:45–58.

    Article  CAS  PubMed  Google Scholar 

  47. Hermans D, Gautam S, Garcia-Canaveras JC, Gromer D, Mitra S, Spolski R, et al. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8(+) T cell stemness and antitumor immunity. Proc Natl Acad Sci USA. 2020;117:6047–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Daniele S, Giacomelli C, Zappelli E, Granchi C, Trincavelli ML, Minutolo F, et al. Lactate dehydrogenase-A inhibition induces human glioblastoma multiforme stem cell differentiation and death. Sci Rep. 2015;5:15556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Oshima N, Ishida R, Kishimoto S, Beebe K, Brender JR, Yamamoto K, et al. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep. 2020;30:1798–810 e1794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rai G, Urban DJ, Mott BT, Hu X, Yang SM, Benavides GA, et al. Pyrazole-based lactate dehydrogenase inhibitors with optimized cell activity and pharmacokinetic properties. J Med Chem. 2020;63:10984–1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324:261–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mellinghoff I, Maher E, Wen P, Cloughesy T, Peters K, Choi C, et al. Rbtt-03. A Phase 1, multicenter, randomized, open-label, perioperative study of Ag-120 (Ivosidenib) and Ag-881 in patients with recurrent, nonenhancing, Idh1-mutant, low-grade glioma. Neuro Oncol. 2018;20:vi234.

    Article  PubMed Central  Google Scholar 

  55. Tejera D, Kushnirsky M, Gultekin SH, Lu M, Steelman L, de la Fuente MI. Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1-mutant glioblastoma: a case report from a Phase I study. CNS Oncol. 2020;9:CNS62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell. 2018;175:101–16 e125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jiang J, Srivastava S, Zhang J. Starve cancer cells of glutamine: break the spell or make a hungry monster? Cancers. 2019;11:1231. https://doi.org/10.3390/cancers11091231.

  58. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018;24:1192–203.

    Article  CAS  PubMed  Google Scholar 

  61. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604.

    Article  CAS  PubMed  Google Scholar 

  62. Grzywa TM, Sosnowska A, Matryba P, Rydzynska Z, Jasinski M, Nowis D, et al. Myeloid cell-derived arginase in cancer immune response. Front Immunol. 2020;11:938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Bossman SA, Ter Laan M, et al. Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function. Neuro Oncol. 2016;18:1253–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42 e813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol. 2011;13:591–9.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Steggerda SM, Bennett MK, Chen J, Emberley E, Huang T, Janes JR, et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017;5:101.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Papadopoulos KP, Tsai FY-C, Bauer TM, Muigai L, Liang Y, Bennett MK, et al. CX-1158-101: a first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors. J Clin Oncol. 2017;35:3005.

    Article  Google Scholar 

  68. Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon K-S, Auffinger B, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18:6110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. J Immunother Cancer. 2015;3:51.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Sosman JA, et al. Immunosuppressive IDO in cancer: mechanisms of action, animal models, and targeting strategies. Front Immunol. 2020;11:1185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology. 2012;1:1460–8.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269–74.

    Article  CAS  PubMed  Google Scholar 

  74. Mitsuka K, Kawataki T, Satoh E, Asahara T, Horikoshi T, Kinouchi H. Expression of indoleamine 2,3-dioxygenase and correlation with pathological malignancy in gliomas. Neurosurgery. 2013;72:1031–8.

    Article  PubMed  Google Scholar 

  75. Hanihara M, Kawataki T, Oh-Oka K, Mitsuka K, Nakao A, Kinouchi H. Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model. J Neurosurg. 2016;124:1594–601.

    Article  CAS  PubMed  Google Scholar 

  76. Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, Dalle S, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 2019;20:1083–97.

    Article  CAS  PubMed  Google Scholar 

  77. Perez RP, Riese MJ, Lewis KD, Saleh MN, Daud A, Berlin J, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204. J Clin Oncol. 2017;35:3003.

    Article  Google Scholar 

  78. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103:13132–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer. Nat Rev Immunol. 2020;20:739–55.

    Article  CAS  PubMed  Google Scholar 

  80. Bullen JW, Tchernyshyov I, Holewinski RJ, DeVine L, Wu F, Venkatraman V, et al. Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1. Sci Signal. 2016;9:ra56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Bavaresco L, Bernardi A, Braganhol E, Cappellari AR, Rockenbach L, Farias PF, et al. The role of ecto-5’-nucleotidase/CD73 in glioma cell line proliferation. Mol Cell Biochem. 2008;319:61–8.

    Article  CAS  PubMed  Google Scholar 

  82. Yan A, Joachims ML, Thompson LF, Miller AD, Canoll PD, Bynoe MS. CD73 promotes glioblastoma pathogenesis and enhances its chemoresistance via A2B adenosine receptor signaling. J Neurosci. 2019;39:4387–402.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Sheth S, Brito R, Mukherjea D, Rybak LP, Ramkumar V. Adenosine receptors: expression, function and regulation. Int J Mol Sci. 2014;15:2024–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Xu S, Shao QQ, Sun JT, Yang N, Xie Q, Wang DH, et al. Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro Oncol. 2013;15:1160–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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:e134386. https://doi.org/10.1172/jci.insight.134386.

  88. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76.

    Article  CAS  PubMed  Google Scholar 

  89. Huang L, Xu H, Peng G. TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy. Cell Mol Immunol. 2018;15:428–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kees T, Lohr J, Noack J, Mora R, Gdynia G, Todt G, et al. Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation. Neuro Oncol. 2012;14:64–78.

    Article  CAS  PubMed  Google Scholar 

  91. De Waele J, Marcq E, Van Audenaerde JR, Van Loenhout J, Deben C, Zwaenepoel K, et al. Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade. Oncoimmunology. 2018;7:e1407899.

    Article  PubMed  Google Scholar 

  92. Kyi C, Roudko V, Sabado R, Saenger Y, Loging W, Mandeli J, et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin Cancer Res. 2018;24:clincanres.1866.2017.

  93. Rosenfeld MR, Chamberlain MC, Grossman SA, Peereboom DM, Lesser GJ, Batchelor TT, et al. A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro Oncol. 2010;12:1071–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gupta S, Grilley-Olson J, Hong D, Marabelle A, Munster P, Aggarwal R, et al. Abstract CT091: safety and pharmacodynamic activity of MEDI9197, a TLR 7/8 agonist, administered intratumorally in subjects with solid tumors. Cancer Res. 2017;77:CT091.

  95. Siu L, Brody J, Gupta S, Marabelle A, Jimeno A, Munster P, et al. Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. J Immunother Cancer. 2020;8:e001095. https://doi.org/10.1136/jitc-2020-001095.

  96. Nayak L, Molinaro AM, Peters K, Clarke JL, Jordan JT, de Groot J, et al. Randomized phase II and biomarker study of pembrolizumab plus bevacizumab versus pembrolizumab alone for patients with recurrent glioblastoma. Clin Cancer Res. 2021;27:1048–57.

    Article  CAS  PubMed  Google Scholar 

  97. 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.

    Article  PubMed  Google Scholar 

  98. Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18:1373–85.

    Article  CAS  PubMed  Google Scholar 

  99. Bernstock JD, Vicario N, Rong L, Valdes PA, Choi BD, Chen JA, et al. A novel in situ multiplex immunofluorescence panel for the assessment of tumor immunopathology and response to virotherapy in pediatric glioblastoma reveals a role for checkpoint protein inhibition. Oncoimmunology. 2019;8:e1678921.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Totsch SK, Schlappi C, Kang KD, Ishizuka AS, Lynn GM, Fox B, et al. Oncolytic herpes simplex virus immunotherapy for brain tumors: current pitfalls and emerging strategies to overcome therapeutic resistance. Oncogene. 2019;38:6159–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas. N Engl J Med. 2021;384:1613–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Olsen HE, Lynn GM, Valdes PA, Cerecedo Lopez CD, Ishizuka AS, Arnaout O, et al. Therapeutic cancer vaccines for pediatric malignancies: advances, challenges, and emerging technologies. Neurooncol Adv. 2021;3:vdab027.

    PubMed  PubMed Central  Google Scholar 

  103. Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Normolle DP, et al. Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro Oncol. 2016;18:1157–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Muller S, Agnihotri S, Shoger KE, Myers MI, Smith N, Chaparala S, et al. Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas. JCI Insight. 2018;3:e98791. https://doi.org/10.1172/jci.insight.98791.

  105. Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

GKF is supported by grants from the U.S. Food and Drug Administration (R01FD005379 and R01FD006368), the Rally Foundation for Childhood Cancer Research, Hyundai Hope on Wheels, Andrew McDonough B+ Foundation, and Cannonball Kids’ cancer Foundation. LP-J has been supported by a senior research fellowship FISM—Fondazione Italiana Sclerosi Multipla—cod. 2017/B/5 and financed or co financed with the “5 per mille” public funding, a Wellcome Trust CRCD Fellowship (RG G105713), and the Addenbrooke’s Charitable Trust (RG 97519). EMT is supported by the Department of Defense (CA171067), The Musella Foundation for Brain Tumor Research and Information, and the Pediatric Brain Tumor Foundation. We thank Adam A. Dmytriw for reviewing the manuscript.

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  1. These authors contributed equally: Joshua D. Bernstock, Kyung-Don Kang.

Authors and Affiliations

  1. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joshua D. Bernstock, Neil V. Klinger, Hannah E. Olsen & David Segar

  2. Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Kyung-Don Kang, Stacie K. Totsch & Gregory K. Friedman

  3. Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, USA

    Sam Gary & Gelare Ghajar-Rahimi

  4. Department of Neurosurgery, Duke University, Durham, NC, USA

    Eric M. Thompson

  5. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Victor Darley-Usmar

  6. Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA

    Bryan T. Mott

  7. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Luca Peruzzotti-Jametti

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  1. Joshua D. Bernstock
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Contributions

All authors contributed to writing, editing, and/or reviewing/revising the manuscript.

Corresponding authors

Correspondence to Joshua D. Bernstock or Gregory K. Friedman.

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Competing interests

JDB has an equity position in Treovir LLC, an oHSV clinical stage company and is a member of the POCKiT Diagnostics Board of Scientific Advisors. The remaining authors declared that no conflict of interest exists.

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Bernstock, J.D., Kang, KD., Klinger, N.V. et al. Targeting oncometabolism to maximize immunotherapy in malignant brain tumors. Oncogene 41, 2663–2671 (2022). https://doi.org/10.1038/s41388-022-02312-y

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