Veranderingen in de immunobiologie van maligne hersentumoren door radiotherapie, chemotherapie en immuuntherapie

Roxanne Wouters
Deze thesis onderzoekt de immunologische effecten van radiotherapie, chemotherapie en immuuntherapie op glioblastoma in een experimentele setting, zowel als individuele behandeling als in verschillende combinaties. Dit geeft ons belangrijke informatie over de eventuele reden voor het falen van huidige experimentele behandelingen in de kliniek.

Kanker in onze hersenen: hoe kan het immuunsysteem helpen?

Hoe komt het dat de huidige behandelingsstrategie voor glioblastoma, de meest agressieve hersentumor, niet in staat is patiënten te genezen en wat is de belangrijke rol van het immuunsysteem in dit verhaal?

Wat is glioblastoma?

Glioblastoma is de meest voorkomende en meest agressieve vorm van kanker in onze hersenen. Het is gelukkig zeldzaam, slechts 500 patiënten in België per jaar, maar de ziekte treft ook jonge kinderen. De standaardbehandeling bestaat uit een operatie waarbij de kanker zo goed mogelijk wordt weggesneden, gevolgd door een combinatie van bestralingen (radiotherapie) en chemotherapie (in de vorm van Temozolomide). Ondanks het intensieve karakter van deze behandeling, is ze tot op heden niet in staat om patiënten te genezen. Glioblastoma patiënten hebben daarom een zeer slechte overleving van gemiddeld 14 maanden. Verschillende onderzoekers zijn om deze reden al een lange tijd op zoek naar een nieuwe en betere behandeling die de vooruitzichten voor deze patiënten in sterke mate zou kunnen verbeteren.

Wat is de rol van het immuunsysteem in dit verhaal?

Het immuunsysteem in ons lichaam zorgt ervoor dat we ons kunnen verdedigen tegen een waaier aan ziektes veroorzaakt door virussen (bijvoorbeeld griep) of bacteriën (bijvoorbeeld een longontsteking), maar eigenlijk kan het immuunsysteem ook beschermen tegen kanker. Het bestaat uit een reeks verschillende cellen die elk een andere belangrijke functie uitoefenen. Al die verschillende cellen werken gecoördineerd samen om kankercellen te herkennen en uit de weg te ruimen.

Hoe komt het dan dat er toch een tumor kan uitgroeien? Tumorcellen zijn slim en kunnen zich zeer goed aanpassen aan hun omgeving. Ze kunnen hun uiterlijke kenmerken veranderen zodat ze bijna onherkenbaar worden voor ons immuunsysteem, een fenomeen dat we immuun onderdrukking noemen. Eén van de manieren waarop kankercellen ons immuunsysteem kunnen ontwijken, is bijvoorbeeld door het aanmaken van een molecule genaamd PD-L1. Dit molecule blokkeert de werking van immuuncellen, die normaal in staat zouden zijn een kankercel uit de weg te ruimen. Dit is ook wat zich voordoet bij glioblastoma. Deze agressieve kankercellen zijn specialisten in het zich verstoppen voor ons immuunsysteem, wat het natuurlijk moeilijk maakt voor ons lichaam om hier op te reageren. Deze complexe wisselwerking tussen het immuunsysteem en kankercellen maakt het voor onderzoekers een serieuze uitdaging om een nieuwe behandeling te vinden. 

Welke nieuwe therapieën zouden ons kunnen helpen?

De laatste jaren zijn verschillende onderzoeksgroepen druk bezig geweest om nieuwe therapieën te ontwikkelen die het immuunsysteem opnieuw kunnen activeren tegen die kankercellen. Eén zo een strategie is de ontwikkeling geweest van immuun checkpoint remmers (anti-PD(L)1). Ze heffen de blokkering op tussen kankercellen en immuuncellen die op basis van PD-L1 tot stand is gekomen. Daardoor zouden de immuuncellen theoretisch terug aan het werk moeten kunnen gaan (omdat ze terug ‘vrij’ zijn) en dus kankercellen moeten kunnen doden. Deze specifieke therapie is zeer succesvol bij huidkanker en longkanker bijvoorbeeld. Het is reeds getest bij glioblastoma patiënten in combinatie met de huidige behandeling (een operatie, bestraling en chemotherapie), maar jammer genoeg kan het succesverhaal van huidkanker en longkanker niet worden doorgetrokken. Mensen met hersenkanker gaan even snel dood, met of zonder deze speciale remmers.

Waarom falen deze therapieën?

Om te weten te komen waarom deze nieuwe combinatie van anti-PD-1 en de standaardbehandeling niet werkt, moeten we nagaan wat er precies gebeurt in patiënten met een hersentumor. Om deze informatie te verkrijgen, hebben wij muizen met hersentumoren bestudeerd en gekeken hoe zij reageren op al deze therapieën. Dit is een cruciale stap om aan het licht te brengen wat er zich bij de mens afspeelt. In dit onderzoek zijn wij te weten gekomen dat alle behandelingen (zowel de bestraling, de chemotherapie en de anti-PD-1) afzonderlijk een zeer uitgesproken effect hebben.

Zo hebben we kunnen vaststellen dat bestraling het grootste immuun stimulerende effect heeft. Dit betekent dat het immuunsysteem een enorme boost krijgt en dus beter kan gaan werken. Dit positieve effect op het immuunsysteem vertaalt zich ook in het feit dat muizen die bestraald worden, langer leven. Chemotherapie daarentegen veroorzaakt echter het tegengestelde effect. Het vermindert de werking van het immuunsysteem en legt het voor een deel lam. Dit gaat zelfs zo ver dat de combinatie van bestraling met chemotherapie (hetgeen elke patiënt momenteel krijgt als standaard behandeling) de positieve effecten van de bestraling volledig teniet doet. Meer nog, dit immuun onderdrukkend effect is zo uitgesproken, dat de immuuntherapie met anti-PD-1 niet in staat is om het immuunsysteem opnieuw te activeren wanneer het in combinatie wordt gegeven met de bestraling en de chemotherapie.

Uit deze resultaten blijkt dat het immuun onderdrukkende effect van de chemotherapie die gebruikt wordt in patiënten met hersentumoren, wel eens de reden zou kunnen zijn waarom anti-PD-1 in de kliniek geen bijkomend voordeel biedt aan deze patiënten. Het toont aan dat het immuunsysteem belangrijker is dan ooit tevoren in het bestrijden van glioblastoma, en bij uitbreiding kanker in het algemeen. De grootste uitdaging in de toekomst voor ons, onderzoekers, zal zijn om de immuun onderdrukkende effecten van de kankercellen om te keren en te zorgen voor een meer immuun stimulerende omgeving in het voordeel van de patiënt.

Bibliografie

1.           American Brain Tumor Association. Glioma [Internet]. 2014 [cited 2017 Oct 25]. Available from: http://www.abta.org/brain-tumor-information/types-of-tumors/glioma.html

2.           Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella‑branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;

3.           Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97–109.

4.           Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015 Jun 6;129(6):829–48.

5.           Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012 Apr 15;26(8):756–84.

6.           Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013 Nov;15 Suppl 2(Suppl 2):ii1-56.

7.           Crocetti E, Trama A, Stiller C, Caldarella A, Soffietti R, Jaal J, et al. Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer. 2012;48:1532–42.

8.           Wen PY, Kesari S. Malignant Gliomas in Adults. N Engl J Med. 2008 Jul 31;359(5):492–507.

9.           Belgian Cancer Registry. Cancer Incidence Projections in Belgium, 2015 to 2025. Brussels; 2017.

10.         Yabroff KR, Harlan L, Zeruto C, Abrams J, Mann B. Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006. Neuro Oncol. 2012 Mar;14(3):351–9.

11.         Woehrer A, Bauchet L, Barnholtz-Sloan JS. Glioblastoma survival: has it improved? Evidence from population-based studies.

12.         Stupp R, Hegi ME, Mason WP, Van Den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.

13.         Dirven L, Aaronson NK, Heimans JJ, Taphoorn MJB. Health-related quality of life in high-grade glioma patients. Chin J Cancer. 2014 Jan;33(1):40–5.

14.         Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med. 2015 Jun;3(9):121.

15.         Omuro A, DeAngelis LM. Glioblastoma and Other Malignant Gliomas. JAMA. 2013 Nov 6;310(17):1842.

16.         Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5):S2-8.

17.         Urbańska K, Sokołowska J, Szmidt M, Sysa P. Glioblastoma multiforme - an overview. Contemp Oncol (Poznan, Poland). 2014;18(5):307–12.

18.         Baba T, Moriguchi M, Natori Y, Katsuki C, Inoue T, Fukui M. Magnetic resonance imaging of experimental rat brain tumors: histopathological evaluation. Surg Neurol. 1990 Dec;34(6):378–82.

19.         Gao H, Jiang X. Progress on the diagnosis and evaluation of brain tumors. Cancer Imaging. 2013 Dec 11;13(4):466–81.

20.         Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre J-Y. Primary brain tumours in adults. Lancet. 2012 May 26;379(9830):1984–96.

21.         Bulika M, Jancaleka R, Vaniceka J, Skocha A, Mechl M. Potential of MR spectroscopy for assessment of glioma grading. Clin Neurol Neurosurg. 2013 Feb 1;115(2):146–53.

22.         Horská A, Barker PB. Imaging of brain tumors: MR spectroscopy and metabolic imaging. Neuroimaging Clin N Am. 2010 Aug;20(3):293–310.

23.         National Cancer Institute, National Human Genome Research Institute. The Cancer Genome Atlas [Internet]. 2014 [cited 2017 Dec 27]. Available from: https://cancergenome.nih.gov/cancersselected/glioblastomamultiforme

24.         Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Poznan, Poland). 2015;19(1A):A68-77.

25.         Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26;321(5897):1807–12.

26.         Khagi S, Miller CR. Putting “multiforme” back into glioblastoma: intratumoral transcriptome heterogeneity is a consequence of its complex morphology. Neuro Oncol. 2017;

27.         Chen J, McKay RM, Parada LF. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell. 2012 Mar 30;149(1):36–47.

28.         Wirsching H-G, Galanis E, Weller M. Glioblastoma. Vol. 134. Elsevier; 2016. 381-397 p.

29.         Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008 Dec 5;116(6):597–602.

30.         Yang P, Zhang W, Wang Y, Peng X, Chen B, Qiu X, et al. IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget. 2015;6(38).

31.         Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013 May;13(5):345.

32.         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 Feb 15;483(7390):479–83.

33.         Kanemoto M, Shirahata M, Nakauma A, Nakanishi K, Taniguchi K, Kukita Y, et al. Prognostic prediction of glioblastoma by quantitative assessment of the methylation status of the entire MGMT promoter region. BMC Cancer. 2014 Aug 30;14:641.

34.         Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13:707–15.

35.         Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005 Jan 1;109(1):93–108.

36.         Carozza SE, Wrensch M, Miike R, Newman B, Olshan AF, Savitz DA, et al. Occupation and adult gliomas. Am J Epidemiol. 2000 Nov 1;152(9):838–46.

37.         De Roos AJ, Stewart PA, Linet MS, Heineman EF, Dosemeci M, Wilcosky T, et al. Occupation and the risk of adult glioma in the United States. Cancer Causes Control. 2003 Mar;14(2):139–50.

38.         Zheng T, Cantor KP, Zhang Y, Keim S, Lynch CF. Occupational Risk Factors for Brain Cancer: A Population-Based Case-Control Study in Iowa.

39.         Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M, et al. Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst. 2002 Oct 16;94(20):1555–63.

40.         Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet (London, England). 2012 Aug 4;380(9840):499–505.

41.         Braganza MZ, Kitahara CM, Berrington de González A, Inskip PD, Johnson KJ, Rajaraman P. Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review. Neuro Oncol. 2012 Nov;14(11):1316–24.

42.         Prasad G, Haas-Kogan DA. Radiation-induced gliomas. Expert Rev Neurother. 2009 Oct;9(10):1511–7.

43.         Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 2014 Jul;16(7):896–913.

44.         Brenner A V., Linet MS, Fine HA, Shapiro WR, Selker RG, Black PM, et al. History of allergies and autoimmune diseases and risk of brain tumors in adults. Int J Cancer. 2002 May 10;99(2):252–9.

45.         Rolle CE, Sengupta S, Lesniak MS. Mechanisms of Immune Evasion by Gliomas. In Springer, New York, NY; 2012. p. 53–76.

46.         Louveau A, Harris TH, Kipnis J. Revisiting the Mechanisms of CNS Immune Privilege. Trends Immunol. 2015 Oct;36(10):569–77.

47.         Engelhardt B, Ransohoff RM. Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol. 2012 Dec;33(12):579–89.

48.         Razavi S-M, Lee KE, Jin BE, Aujla PS, Gholamin S, Li G. Immune Evasion Strategies of Glioblastoma. Front Surg. 2016;3:11.

49.         Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017 May 1;77(9):2266–78.

50.         Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Bossman SAJFH, 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 Sep;18(9):1253–64.

51.         Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, et al. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res. 2008 Aug 15;14(16):5166–72.

52.         Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B. Immune microenvironment of gliomas. Lab Investig. 2017 May 13;97(5):498–518.

53.         Domingues P, González-Tablas M, Otero Á, Pascual D, Miranda D, Ruiz L, et al. Tumor infiltrating immune cells in gliomas and meningiomas. 2016;

54.         Ma Y, Shurin G V, Peiyuan Z, Shurin MR. Dendritic cells in the cancer microenvironment. J Cancer. 2013;4(1):36–44.

55.         Abbas AK, Lichtman AH, Pillai S. Basic Immunology: Functions and Disorders of the Immune System. 4th ed. Elsevier; 2012.

56.         Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002 26. 2002 Jun 1;2(6):389.

57.         von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005 Apr 1;6(4):338–44.

58.         Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998 Jul 20;188(2):287–96.

59.         Han S, Zhang C, Li Q, Dong J, Liu Y, Huang Y, et al. Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma. Br J Cancer. 2014 May 13;110(10):2560–8.

60.         Maes W, Verschuere T, Van Hoylandt A, Boon L, Van Gool S. Depletion of regulatory T cells in a mouse experimental glioma model through anti-CD25 treatment results in the infiltration of non-immunosuppressive myeloid cells in the brain. Clin Dev Immunol. 2013;2013:952469.

61.         Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro Oncol. 2012 May;14(5):584–95.

62.         Perng P, Lim M. Immunosuppressive Mechanisms of Malignant Gliomas: Parallels at Non-CNS Sites. Front Oncol. 2015;5:153.

63.         Wischhusen J, Jung G, Radovanovic I, Beier C, Steinbach JP, Rimner A, et al. Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res. 2002 May 1;62(9):2592–9.

64.         Dubinski D, Wölfer J, Hasselblatt M, Schneider-Hohendorf T, Bogdahn U, Stummer W, et al. CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol. 2016;18(6):807–18.

65.         Huang B, Zhang H, Gu L, Ye B, Jian Z, Stary C, et al. Advances in Immunotherapy for Glioblastoma Multiforme. J Immunol Res. 2017;2017:3597613.

66.         Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015 Aug;17(8):1064–75.

67.         Hutarew G. PD-L1 testing, fit for routine evaluation? From a pathologist’s point of view. memo - Mag Eur Med Oncol. 2016 Dec 28;9(4):201–6.

68.         van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med. 1997 Feb 3;185(3):393–403.

69.         Huang J, Liu F, Liu Z, Tang H, Wu H, Gong Q, et al. Immune Checkpoint in Glioblastoma: Promising and Challenging. Front Pharmacol. 2017;8:242.

70.         Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009 Aug 3;206(8):1717–25.

71.         Uyttenhove C, Pilotte L, Théate 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 Oct 21;9(10):1269–74.

72.         Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999 Oct 1;20(10):469–73.

73.         Wainwright DA, Balyasnikova I V, 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 Nov 15;18(22):6110–21.

74.         Jansen T, Tyler B, Mankowski JL, Recinos VR, Pradilla G, Legnani F, et al. FasL gene knock-down therapy enhances the antiglioma immune response. Neuro Oncol. 2010 May;12(5):482–9.

75.         Zhang B, Sun T, Xue L, Han X, Zhang B, Lu N, et al. Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer. Carcinogenesis. 2006 Nov 27;28(5):1067–73.

76.         Saggioro FP, Neder L, Stávale JN, Paixão-Becker ANP, Malheiros SMF, Soares FA, et al. Fas, FasL, and cleaved caspases 8 and 3 in glioblastomas: A tissue microarray-based study. Pathol - Res Pract. 2014 May 1;210(5):267–73.

77.         Andaloussi A El, Lesniak MS. An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme1. Neuro Oncol. 2006 Jul 1;8(3):234–43.

78.         Thomas AA, Fisher JL, Rahme GJ, Hampton TH, Baron U, Olek S, et al. Regulatory T cells are not a strong predictor of survival for patients with glioblastoma. Neuro Oncol. 2015 Jun;17(6):801–9.

79.         Paul S, Lal G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front Immunol. 2017;8:1124.

80.         Stevens A, Klöter I, Roggendorf W. Inflammatory infiltrates and natural killer cell presence in human brain tumors. Cancer. 1988 Feb 15;61(4):738–43.

81.         Yang I, Han SJ, Sughrue ME, Tihan T, Parsa AT. Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology. J Neurosurg. 2011 Sep 1;115(3):505–11.

82.         Kmiecik J, Poli A, Brons NHC, Waha A, Eide GE, Enger Ø, et al. Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol. 2013;264:71–83.

83.         Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, et al. NK Cells Recognize and Kill Human Glioblastoma Cells with Stem Cell-Like Properties 1.

84.         Tsou P, Katayama H, Ostrin EJ, Hanash SM. The Emerging Role of B Cells in Tumor Immunity. Cancer Res. 2016 Oct 1;76(19):5597–601.

85.         Candolfi M, Curtin JF, Yagiz K, Assi H, Wibowo MK, Alzadeh GE, et al. B cells are critical to T-cell-mediated antitumor immunity induced by a combined immune-stimulatory/conditionally cytotoxic therapy for glioblastoma. Neoplasia. 2011 Oct;13(10):947–60.

86.         Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. 2010 Nov 1;185(9):4977–82.

87.         Sarvaria A, Madrigal JA, Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol. 2017 Aug;14(8):662–74.

88.         Ye Z, He H, Wang H, Li W, Luo L, Huang Z, et al. Glioma-derived ADAM10 induces regulatory B cells to suppress CD8+ T cells. PLoS One. 2014;9(8):e105350.

89.         Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014 Aug 13;6(3):1670–90.

90.         Hao N-B, Lü M-H, Fan Y-H, Cao Y-L, Zhang Z-R, Yang S-M. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.

91.         Debinski W, Rodriguez A, Gibo D, Tatter SB, Mott R, Lively M, et al. FUNCTIONAL PRESENCE OF M2 MACROPHAGE MARKERS IN GBM TUMOR CELLS. Neuro Oncol. 2014 Jul 1;16(suppl 3):iii40-iii41.

92.         Hong T-M, Teng L-J, Shun C-T, Peng M-C, Tsai J-C. Induced interleukin-8 expression in gliomas by tumor-associated macrophages. J Neurooncol. 2009 Jul 21;93(3):289–301.

93.         Zhang B, Yao G, Zhang Y, Gao J, Yang B, Rao Z, et al. M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo). 2011;66(11):1879–86.

94.         Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010 Aug;10(8):554–67.

95.         Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol. 2010 Apr;22(2):231–7.

96.         Thomas DA, Massagué J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005 Nov;8(5):369–80.

97.         Galarneau H, Villeneuve J, Gowing G, Julien J-P, Vallières L. Increased glioma growth in mice depleted of macrophages. Cancer Res. 2007 Sep 15;67(18):8874–81.

98.         Kohanbash G, Okada H. Myeloid-derived Suppressor Cells (MDSCs) in Gliomas and Glioma-Development. Immunol Invest. 2012 Aug 27;41(6–7):658–79.

99.         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 Jun;13(6):591–9.

100.      Wyczechowska D, Hernandez C, Zheng L, Rodriguez P, Ochoa A. The journal of immunology : official journal of the American Association of Immunologists. Vol. 194, The Journal of Immunology. Williams & Wilkins; 1950. 141.19-141.19.

101.      Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013 Feb;138(2):105–15.

102.      Raychaudhuri B, Rayman P, Huang P, Grabowski M, Hambardzumyan D, Finke JH, et al. Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes. J Neurooncol. 2015 Apr 13;122(2):293–301.

103.      Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, et al. Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer. J Immunol. 2001;166:678–89.

104.      Chang AL, Miska J, Wainwright DA, Dey M, Rivetta C V, Yu D, et al. CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer Res. 2016 Oct 1;76(19):5671–82.

105.      Jia W, Jackson-Cook C, Graf MR. Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. J Neuroimmunol. 2010 Jun;223(1–2):20–30.

106.      Alizadeh D, Zhang L, Brown CE, Farrukh O, Jensen MC, Badie B. Induction of Anti-Glioma Natural Killer Cell Response following Multiple Low-Dose Intracerebral CpG Therapy. Clin Cancer Res. 2010 Jul 1;16(13):3399–408.

107.      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;35210.

108.      Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the Extent of Resection With Survival in Glioblastoma. JAMA Oncol. 2016 Nov 1;2(11):1460.

109.      Bloch O, Han SJ, Cha S, Sun MZ, Aghi MK, McDermott MW, et al. Impact of extent of resection for recurrent glioblastoma on overall survival. J Neurosurg. 2012 Dec;117(6):1032–8.

110.      Hadjipanayis CG, Widhalm G, Stummer W. What is the Surgical Benefit of Utilizing 5-Aminolevulinic Acid for Fluorescence-Guided Surgery of Malignant Gliomas? Neurosurgery. 2015 Nov;77(5):663–73.

111.      Walker MD, Alexander E, Hunt WE, MacCarty CS, Mahaley MS, Mealey J, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg. 1978 Sep 7;49(3):333–43.

112.      Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Inr J Rodiarion Oncol Biol Phys. 1979;5:25–1731.

113.      Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS. Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr. 1988;(6):279–84.

114.      Wind JJ, Young R, Saini A, Sherman JH. The Role of Adjuvant Radiation Therapy in the Management of High-Grade Gliomas. Neurosurg Clin N Am. 2012 Apr 1;23(2):247–58.

115.      Hau E, Shen H, Clark C, Graham PH, Koh E-S, L. McDonald K. The evolving roles and controversies of radiotherapy in the treatment of glioblastoma. J Med Radiat Sci. 2016 Jun 1;63(2):114–23.

116.      Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol. 1989 Jun 1;16(6):1405–9.

117.      Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M;, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol. 2008;26(2625).

118.      Zhang J, Stevens MFG, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012 Jan;5(1):102–14.

119.      National Cancer Institute (NIH). FDA Approval for Temozolomide - National Cancer Institute [Internet]. [cited 2017 Dec 27]. Available from: https://www.cancer.gov/about-cancer/treatment/drugs/fda-temozolomide

120.      Patel M, McCully C, Godwin K, Balis FM. Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Temozolomide in Non-human Primates. J Neurooncol. 2003;61(3):203–7.

121.      Friedman HS, Dolan ME, Pegg AE, Marcelli S, Keir S, Catino JJ, et al. Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res. 1995 Jul 1;55(13):2853–7.

122.      Kitange GJ, Carlson BL, Schroeder MA, Grogan PT, Lamont JD, Decker PA, et al. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol. 2009 Jun;11(3):281–91.

123.      Roux A, Peeters S, Zanello M, Bou Nassif R, Abi Lahoud G, Dezamis E, et al. Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice. J Neurooncol. 2017 Oct 1;135(1):83–92.

124.      Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma 1,2. Neuro-Oncology I. 2003;

125.      Zhang Y-D, Dai R-Y, Chen Z, Zhang Y-H, He X-Z, Zhou J, et al. Efficacy and Safety of Carmustine Wafers in the Treatment of Glioblastoma Multiforme: A Systematic Review. Turk Neurosurg. 2014;24(5):639–45.

126.      Jeong H, Bok S, Hong B-J, Choi H-S, Ahn G-O. Radiation-induced immune responses: mechanisms and therapeutic perspectives. Blood Res. 2016 Sep;51(3):157–63.

127.      Bloy N, Pol J, Manic G, Vitale I, Eggermont A, Galon J, et al. Trial Watch: Radioimmunotherapy for oncological indications. Oncoimmunology. 2014 Oct;3(9):e954929.

128.      Manda K, Glasow A, Paape D, Hildebrandt G. Effects of ionizing radiation on the immune system with special emphasis on the interaction of dendritic and T cells. Front Oncol. 2012;2:102.

129.      Falcke S, Frey B, Rühle PF, Gaipl US. Human peripheral blood immune cells strongly differ in their radiosensitivity. In 2015.

130.      Deloch L, Derer A, Hartmann J, Frey B, Fietkau R, Gaipl US. Modern Radiotherapy Concepts and the Impact of Radiation on Immune Activation. Front Oncol. 2016;6:141.

131.      Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol. 2012;2:191.

132.      Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, et al. Phase I Trial of Temozolomide Using an Extended Continuous Oral Schedule. CANCER Res. 1998;58:4363–7.

133.      Reese JS, Qin X, Ballas CB, Sekiguchi M, Gerson SL. MGMT Expression in Murine Bone Marrow Is a Major Determinant of Animal Survival After Alkylating Agent Exposure. J Hematother Stem Cell Res. 2001 Feb;10(1):115–23.

134.      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 Mar;13(3):324–33.

135.      Sanchez-Perez LA, Choi BD, Archer GE, Cui X, Flores C, Johnson LA, et al. Myeloablative temozolomide enhances CD8+ T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS One. 2013;8(3):e59082.

136.      Park S-D, Kim C-H, Kim C-K, Park J-A, Sohn H-J, Hong Y-K, et al. Cross-priming by temozolomide enhances antitumor immunity of dendritic cell vaccination in murine brain tumor model. Vaccine. 2007 Apr 30;25(17):3485–91.

137.      Fadul CE, Fisher JL, Gui J, Hampton TH, Côté AL, Ernstoff MS. Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme. Neuro Oncol. 2011 Apr;13(4):393–400.

138.      Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based immunotherapy. Cell Res. 2017 Jan 27;27(1):74–95.

139.      Shah AH, Bregy A, Heros DO, Komotar RJ, Goldberg J. Dendritic Cell Vaccine for Recurrent High-Grade Gliomas in Pediatric and Adult Subjects. Neurosurgery. 2013 Nov 1;73(5):863–7.

140.      Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007 Apr 1;13(7):2158–67.

141.      Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013 Jun 1;86(2):343–9.

142.      Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res. 2016 Feb 1;4(2):124–35.

143.      Filley AC, Henriquez M, Dey M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget. 2017 Oct 31;8(53):91779–94.

144.      Maxwell R, Jackson CM, Lim M. Clinical Trials Investigating Immune Checkpoint Blockade in Glioblastoma. Curr Treat Options Oncol. 2017 Aug 7;18(8):51.

145.      Dolcetti L, Peranzoni E, Ugel S, Marigo I, Fernandez Gomez A, Mesa C, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol. 2009 Nov 25;40(1):22–35.

146.      Youn J-I, Gabrilovich DI. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol. 2010 Nov;40(11):2969–75.

147.      Dejaegher J, Verschuere T, Vercalsteren E, Boon L, Cremer J, Sciot R, et al. Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade. Int J Cancer. 2017 Nov 1;141(9):1891–900.

148.      Campian JL, Piotrowski AF, Ye X, Hakim FT, Rose J, Yan X-Y, et al. Serial changes in lymphocyte subsets in patients with newly diagnosed high grade astrocytomas treated with standard radiation and temozolomide. J Neurooncol. 2017 Nov 29;135(2):343–51.

149.      Karachi A, Dastmalchi F, Mitchell D, Rahman M. Temozolomide for Immunomodulation in the Treatment of Glioblastoma. Neuro Oncol. 2018 May 4;

150.      Cui X, Morales R-TT, Qian W, Wang H, Gagner J-P, Dolgalev I, et al. Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. Biomaterials. 2018 Apr 1;161:164–78.

151.      Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010 Oct 20;11(10):889–96.

152.      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(2).

153.      Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Petersen-Baltussen HMJM, ter Laan M, et al. Increase in Both CD14-Positive and CD15-Positive Myeloid-Derived Suppressor Cell Subpopulations in the Blood of Patients With Glioma But Predominance of CD15-Positive Myeloid-Derived Suppressor Cells in Glioma Tissue. J Neuropathol Exp Neurol. 2015 May 1;74(5):390–400.

154.      Zhu X, Fujita M, Snyder LA, Okada H. Systemic Delivery of Neutralizing Antibody Targeting CCL2 for Glioma Therapy.

Universiteit of Hogeschool
Master in de Biomedische Wetenschappen
Publicatiejaar
2018
Promotor(en)
An Coosemans, Matteo Riva
Kernwoorden