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Journal of Neuro-Oncology

, Volume 132, Issue 3, pp 359–372 | Cite as

Immune checkpoint inhibition and its relationship with hypermutation phenoytype as a potential treatment for Glioblastoma

  • Manohan Sinnadurai
  • Kerrie L. McDonald
Topic Review

Abstract

Glioblastoma (GBM) is the most common malignant brain tumour in adults. Current prognosis with standard treatment is poor. Immunotherapy is a new paradigm in tumour management. Specifically, recent advances in the field of immune checkpoint molecules have led to dramatic results in many cancers. Inhibition of one particular, programmed cell death—1 (PD-1) has recently been shown to be highly effective in melanoma and non-small cell lung cancer. There has also been recent data to suggest potential benefit in GBM. There also appears to be a relationship between immune checkpoint inhibition and hypermutation, in particular with the mismatch repair process. In this review we look at the current knowledge of immune checkpoint inhibitors with a focus on the PD-1 pathway. We will also review the evidence of PD-1 inhibition in GBM and the role of hypermutation in PD-1 inhibition.

Keywords

Immune checkpoint Glioblastoma PD-1 PD-L1 Mismatch repair 

References

  1. 1.
    AIHW C (2014) Cancer in Australia: an overview 2014.Google Scholar
  2. 2.
  3. 3.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. doi: 10.1056/NEJMra0708126 PubMedCrossRefGoogle Scholar
  4. 4.
    Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193. doi: 10.3322/caac.20069 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27PubMedCrossRefGoogle Scholar
  6. 6.
    Bobisse S, Foukas PG, Coukos G, Harari A (2016) Neoantigen-based cancer immunotherapy. Ann Transl Med 4(14):262. doi: 10.21037/atm.2016.06.17 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. doi: 10.1016/j.immuni.2004.07.017 PubMedCrossRefGoogle Scholar
  8. 8.
    Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer immunoediting and its three component phases — elimination, equilibrium and escape. Curr Opin Immunol 27:16–25. doi: 10.1016/j.coi.2014.01.004 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296. doi: 10.1146/annurev.immunol.25.022106.141609 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Coley BW (1893) The treatment of malignat tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 105(5):487–510CrossRefGoogle Scholar
  11. 11.
    Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA, Sullivan J, Sarosdy MF, Crissman JD, Coltman CA (1991) A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette–Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 325(17):1205–1209. doi: 10.1056/NEJM199110243251703 PubMedCrossRefGoogle Scholar
  12. 12.
    Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13(3):688–696PubMedCrossRefGoogle Scholar
  13. 13.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105PubMedCrossRefGoogle Scholar
  14. 14.
    Alegre M-L, Frauwirth KA, Thompson CB (2001) T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1(3):220–228PubMedCrossRefGoogle Scholar
  15. 15.
    Chen L (2004) Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4(5):336–347PubMedCrossRefGoogle Scholar
  16. 16.
    Bluestone JA (2011) Mechanisms of tolerance. Immunol Rev 241(1):5–19. doi: 10.1111/j.1600-065X.2011.01019.x PubMedCrossRefGoogle Scholar
  17. 17.
    Salomon B, Bluestone JA (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225–252. doi: 10.1146/annurev.immunol.19.1.225 PubMedCrossRefGoogle Scholar
  18. 18.
    Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987) A new member of the immunoglobulin superfamily–CTLA-4. Nature 328(6127):267–270. doi: 10.1038/328267a0 PubMedCrossRefGoogle Scholar
  19. 19.
    Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M (2005) Resting dendritic cells induce peripheral CD8 + T cell tolerance through PD-1 and CTLA-4. Nat Immunol 6(3):280–286PubMedCrossRefGoogle Scholar
  20. 20.
    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270(5238):985–988PubMedCrossRefGoogle Scholar
  21. 21.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547. doi: 10.1016/1074-7613(95)90125-6 PubMedCrossRefGoogle Scholar
  22. 22.
    Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939):506–511. doi: 10.1038/nature01621 PubMedCrossRefGoogle Scholar
  23. 23.
    Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13(4):227–242. doi: 10.1038/nri3405 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11):3887–3895PubMedPubMedCentralGoogle Scholar
  25. 25.
    Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5(12):1365–1369. doi: 10.1038/70932 PubMedCrossRefGoogle Scholar
  26. 26.
    Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268. doi: 10.1038/85330 PubMedCrossRefGoogle Scholar
  27. 27.
    Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA (2012) Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 5 (230):ra46–ra46PubMedCrossRefGoogle Scholar
  28. 28.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. doi: 10.1146/annurev.immunol.26.021607.090331 PubMedCrossRefGoogle Scholar
  29. 29.
    Jin H-T, Ahmed R, Okazaki T (2011) Role of PD-1 in regulating T-cell immunity. In: Ahmed R, Honjo T (eds) Negative co-receptors and ligands. Springer, Berlin, pp 17–37. doi: 10.1007/82_2010_116 Google Scholar
  30. 30.
    Keir ME, Latchman YE, Freeman GJ, Sharpe AH (2005) Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol 175 (11):7372–7379PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Blank C, Brown I, Marks R, Nishimura H, Honjo T, Gajewski TF (2003) Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells. J Immunol 171(9):4574–4581. doi: 10.4049/jimmunol.171.9.4574 PubMedCrossRefGoogle Scholar
  32. 32.
    Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151PubMedCrossRefGoogle Scholar
  33. 33.
    Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H Jr, Sayegh MH (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198(1):63–69. doi: 10.1084/jem.20022125 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291(5502):319–322. doi: 10.1126/science.291.5502.319 PubMedCrossRefGoogle Scholar
  35. 35.
    Okazaki T, Honjo T (2007) PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19(7):813–824. doi: 10.1093/intimm/dxm057 PubMedCrossRefGoogle Scholar
  36. 36.
    Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736. doi: 10.1126/science.271.5256.1734 PubMedCrossRefGoogle Scholar
  37. 37.
    van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med 190(3):355–366PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206(13):3015–3029. doi: 10.1084/jem.20090847 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Allen SJ, Mott KR, Wechsler SL, Flavell RA, Town T, Ghiasi H (2011) Adaptive and innate transforming growth factor β signaling impact herpes simplex virus 1 latency and reactivation. J Virol 85(21):11448–11456. doi: 10.1128/jvi.00678-11 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114(8):1537–1544. doi: 10.1182/blood-2008-12-195792 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, Kirkwood JM, Chen TH, Maurer M, Korman AJ, Zarour HM (2015) TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 125(5):2046–2058. doi: 10.1172/jci80445 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M (2013) Increased PD-1 expression on CD4 + and CD8 + T cells is involved in immune evasion in gastric cancer. J Surg Oncol 107(5):517–522. doi: 10.1002/jso.23281 PubMedCrossRefGoogle Scholar
  43. 43.
    Herbst RS, Soria J-C, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HEK, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567. doi: 10.1038/nature14011 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, Weber WP, Soysal SD (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146(1):15–24. doi: 10.1007/s10549-014-2988-5 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2007) PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 13(6):1757–1761. doi: 10.1158/1078-0432.ccr-06-2599 PubMedCrossRefGoogle Scholar
  46. 46.
    Zhou ZJ, Zhan P, Song Y (2015) PD-L1 over-expression and survival in patients with non-small cell lung cancer: a meta-analysis. Transl Lung Cancer Res 4(2):203–208. doi: 10.3978/j.issn.2218-6751.2015.03.02 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Wu P, Wu D, Li L, Chai Y, Huang J (2015) PD-L1 and survival in solid tumors: a meta-analysis. PLoS ONE 10(6):e0131403. doi: 10.1371/journal.pone.0131403 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggren R, Hemminki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9(5):562–567PubMedCrossRefGoogle Scholar
  49. 49.
    Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ (2010) Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. J Immunol 184(7):3442–3449PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yao L-C, Cheng M, Wang M, Banchereau J, Shultz L, Palucka K, Keck JG (2015) Abstract LB-C01: Patient-derived tumor xenografts in humanized NSG-SGM3 mice: a new immuno-oncology platform. Am Assoc Cancer Res 14 (12 Supplement 2):LB-C01-LB-C01. doi: 10.1158/1535-7163.targ-15-lb-c01 Google Scholar
  51. 51.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363(8):711–723. doi: 10.1056/NEJMoa1003466 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain J-F, Testori A, Grob J-J, Davidson N, Richards J, Maio M, Hauschild A, Miller WHJ, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen T-T, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526. doi: 10.1056/NEJMoa1104621 PubMedCrossRefGoogle Scholar
  53. 53.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of Anti–PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi: 10.1056/NEJMoa1200690 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of Anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi: 10.1056/NEJMoa1200694 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. doi: 10.1056/NEJMoa1504030 PubMedCrossRefGoogle Scholar
  56. 56.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532. doi: 10.1056/NEJMoa1503093 PubMedCrossRefGoogle Scholar
  57. 57.
    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C (2016) Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. ASCO Meeting Abstracts 34 (15_suppl):9504Google Scholar
  58. 58.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao C, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Haanen JBAG, Maio M, McArthur GA, Walker D, Jiang J, Horak CE, Larkin JMG, Hodi FS (2016) Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). ASCO Meeting Abstracts 34 (15_suppl):9505Google Scholar
  59. 59.
    Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob J-J, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) 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 16(4):375–384. doi: 10.1016/S1470-2045(15)70076-8 PubMedCrossRefGoogle Scholar
  60. 60.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GRJ, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373(17):1627–1639. doi: 10.1056/NEJMoa1507643 PubMedCrossRefGoogle Scholar
  61. 61.
    Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 24(12):719–725PubMedCrossRefGoogle Scholar
  62. 62.
    Wolburg H, Wolburg-Buchholz K, Engelhardt B (2005) Diapedesis of mononuclear cells across cerebral venules during experimental autoimmune encephalomyelitis leaves tight junctions intact. Acta Neuropathol 109(2):181–190. doi: 10.1007/s00401-004-0928-x PubMedCrossRefGoogle Scholar
  63. 63.
    Eder K, Kalman B (2015) The dynamics of Interactions among immune and glioblastoma cells. Neuromol Med 17(4):335–352. doi: 10.1007/s12017-015-8362-x CrossRefGoogle Scholar
  64. 64.
    Yang I, Han SJ, Sughrue ME, Tihan T, Parsa AT (2011) Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology. J Neurosurg 115(3):505–511. doi: 10.3171/2011.4.jns101172 PubMedCrossRefGoogle Scholar
  65. 65.
    Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P, Grotenhuis JA, Hoogerbrugge PM, de Vries IJ, Adema GJ (2009) Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro-oncol 11(4):394–402. doi: 10.1215/15228517-2008-104 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Jacobs JF, Idema AJ, Bol KF, Grotenhuis JA, de Vries IJ, Wesseling P, Adema GJ (2010) Prognostic significance and mechanism of Treg infiltration in human brain tumors. J Neuroimmunol 225(1–2):195–199. doi: 10.1016/j.jneuroim.2010.05.020 PubMedCrossRefGoogle Scholar
  67. 67.
    Yang I, Han SJ, Kaur G, Crane C, Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17(1):6–10. doi: 10.1016/j.jocn.2009.05.006 PubMedCrossRefGoogle Scholar
  68. 68.
    Waziri A, Killory B, Ogden AT, Canoll P, Anderson RCE, Kent SC, Anderson DE, Bruce JN (2008) Preferential in situ CD4 + CD56 + T cell activation and expansion within human glioblastoma. J Immunol 180(11):7673–7680. doi: 10.4049/jimmunol.180.11.7673 PubMedCrossRefGoogle Scholar
  69. 69.
    Albesiano E, Han JE, Lim M (2010) Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am 21 (1):17–29. doi: 10.1016/j.nec.2009.08.008 PubMedCrossRefGoogle Scholar
  70. 70.
    Avril T, Vauleon E, Tanguy-Royer S, Mosser J, Quillien V (2011) Mechanisms of immunomodulation in human glioblastoma. Immunotherapy 3 (4 Suppl):42–44. doi: 10.2217/imt.11.39 PubMedCrossRefGoogle Scholar
  71. 71.
    Fecci PE, Heimberger AB, Sampson JH (2014) Immunotherapy for primary brain tumors: no longer a matter of privilege. Clin Cancer Res 20(22):5620–5629. doi: 10.1158/1078-0432.ccr-14-0832 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, Weller M, Wiendl H (2003) Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63(21):7462–7467PubMedGoogle Scholar
  73. 73.
    Wilmotte R, Burkhardt K, Kindler V, Belkouch MC, Dussex G, Tribolet N, Walker PR, Dietrich PY (2005) B7-homolog 1 expression by human glioma: a new mechanism of immune evasion. Neuroreport 16(10):1081–1085PubMedCrossRefGoogle Scholar
  74. 74.
    Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88PubMedCrossRefGoogle Scholar
  75. 75.
    Waldron JS, Yang I, Han S, Tihan T, Sughrue ME, Mills SA, Pieper RO, Parsa AT (2010) Implications for immunotherapy of tumor-mediated T-cell apoptosis associated with loss of the tumor suppressor PTEN in glioblastoma. J Clin Neurosci 17(12):1543–1547. doi: 10.1016/j.jocn.2010.04.021 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT (2013) Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 19(12):3165–3175. doi: 10.1158/1078-0432.CCR-12-3314 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, Dieckmann K, Filipits M, Brandstetter A, Weller M, Kurscheid S, Hegi ME, Zielinski CC, Marosi C, Hainfellner JA, Preusser M, Wick W (2015) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-oncology 17(8):1064–1075. doi: 10.1093/neuonc/nou307 PubMedCrossRefGoogle Scholar
  78. 78.
    Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ, Burks JK, Fuller GN, Calin GA, Conrad CA, Creasy C, Ritthipichai K, Radvanyi L, Heimberger AB (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro-oncology 18(2):195–205. doi: 10.1093/neuonc/nov172 PubMedCrossRefGoogle Scholar
  79. 79.
    Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris TJ, Albesiano E, Pradilla G, Ford E, Wong J, Hammers HJ, Mathios D, Tyler B, Brem H, Tran PT, Pardoll D, Drake CG, Lim M (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86(2):343–349. doi: 10.1016/j.ijrobp.2012.12.025 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, Jones KL, Saur Conway A, Liao X, Zhou J, Wen PY, Van den Abbeele AD, Hodi FS, Qin L, Kohl NE, Sharpe AH, Dranoff G, Freeman GJ (2015) Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. doi: 10.1158/2326-6066.cir-15-0151 PubMedGoogle Scholar
  81. 81.
    Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, Cheng Y, Kim JW, Qiao J, Zhang L, Han Y, Lesniak MS (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4 and PD-L1 in mice with brain tumors. Clin Cancer Res 20(20):5290–5301. doi: 10.1158/1078-0432.CCR-14-0514 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, Zhukova N, Mason G, Farah R, Afzal S, Yalon M, Rechavi G, Magimairajan V, Walsh MF, Constantini S, Dvir R, Elhasid R, Reddy A, Osborn M, Sullivan M, Hansford J, Dodgshun A, Klauber-Demore N, Peterson L, Patel S, Lindhorst S, Atkinson J, Cohen Z, Laframboise R, Dirks P, Taylor M, Malkin D, Albrecht S, Dudley RWR, Jabado N, Hawkins CE, Shlien A, Tabori U (2016) Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. doi: 10.1200/jco.2016.66.6552 Google Scholar
  83. 83.
    Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465. doi: 10.1016/S1470-2045(12)70090-6 PubMedCrossRefGoogle Scholar
  84. 84.
    Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD (2013) Ipilimumab and radiation therapy for melanoma brain metastases. Cancer Med 2(6):899–906. doi: 10.1002/cam4.140 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, Tsiouris AJ, Cohen J, Vortmeyer A, Jilaveanu L, Yu J, Hegde U, Speaker S, Madura M, Ralabate A, Rivera A, Rowen E, Gerrish H, Yao X, Chiang V, Kluger HM (2016) 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. doi: 10.1016/s1470-2045(16)30053-5 Google Scholar
  86. 86.
    Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, Ellingson BM, Hashimoto N, Pollack IF, Brandes AA, Franceschi E, Herold-Mende C, Nayak L, Panigrahy A, Pope WB, Prins R, Sampson JH, Wen PY, Reardon DA (2015) Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol 16(15):e534–e542. doi: 10.1016/S1470-2045(15)00088-1 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Roberts SA, Gordenin DA (2014) Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 14(12):786–800. doi: 10.1038/nrc3816 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Li G-M (2008) Mechanisms and functions of DNA mismatch repair. Cell Res 18(1):85–98PubMedCrossRefGoogle Scholar
  89. 89.
    Kim T-M, Laird PW, Park PJ (2013) The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell. doi: 10.1016/j.cell.2013.10.015 Google Scholar
  90. 90.
    Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337. doi: 10.1038/nature11252 CrossRefGoogle Scholar
  91. 91.
    Timmermann B, Kerick M, Roehr C, Fischer A, Isau M, Boerno ST, Wunderlich A, Barmeyer C, Seemann P, Koenig J, Lappe M, Kuss AW, Garshasbi M, Bertram L, Trappe K, Werber M, Herrmann BG, Zatloukal K, Lehrach H, Schweiger MR (2010) Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PLoS ONE 5(12):e15661. doi: 10.1371/journal.pone.0015661 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134(4):988–997. doi: 10.1053/j.gastro.2008.01.015 PubMedCrossRefGoogle Scholar
  93. 93.
    Woerner SM, Gebert J, Yuan YP, Sutter C, Ridder R, Bork P, von Knebel Doeberitz M (2001) Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. Int J Cancer Journal international du cancer 93(1):12–19PubMedCrossRefGoogle Scholar
  94. 94.
    Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H, Bindea G, Angell HK, Fredriksen T, Elie N, Fauquembergue E, Drouet A, Leprince J, Benichou J, Mauillon J, Le Pessot F, Sesboue R, Tuech JJ, Sabourin JC, Michel P, Frebourg T, Galon J, Latouche JB (2015) Correlation between density of CD8 + T-cell infiltrate in microsatellite unstable colorectal Cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res 75(17):3446–3455. doi: 10.1158/0008-5472.can-14-3051 PubMedCrossRefGoogle Scholar
  95. 95.
    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199. doi: 10.1056/NEJMoa1406498 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128. doi: 10.1126/science.aaa1348 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Geukes Foppen MH, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. doi: 10.1056/NEJMoa1500596 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Castro MP, Goldstein N (2015) Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations. J Immuno Ther Cancer 3(1):1–6. doi: 10.1186/s40425-015-0104-y CrossRefGoogle Scholar
  100. 100.
    Llosa NJ, Cruise M, Tam A, Wick EC, Hechenbleikner EM, Taube JM, Blosser L, Fan H, Wang H, Luber B, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5(1):43–51. doi: 10.1158/2159-8290.CD-14-0863 PubMedCrossRefGoogle Scholar
  101. 101.
    Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13(7):2038–2045. doi: 10.1158/1078-0432.ccr-06-2149 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15(14):4622–4629. doi: 10.1158/1078-0432.ccr-08-3012 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    McFaline-Figueroa JL, Braun CJ, Stanciu M, Nagel ZD, Mazzucato P, Sangaraju D, Cerniauskas E, Barford K, Vargas A, Chen Y, Tretyakova N, Lees JA, Hemann MT, White FM, Samson LD (2015) Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide. Cancer Res 75(15):3127–3138. doi: 10.1158/0008-5472.CAN-14-3616 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Shinsato Y, Furukawa T, Yunoue S, Yonezawa H, Minami K, Nishizawa Y, Ikeda R, Kawahara K, Yamamoto M, Hirano H, Tokimura H, Arita K (2013) Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma. Oncotarget 4(12):2261–2270PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, Schackert G, Kreth FW, Pietsch T, Loffler M, Weller M, Reifenberger G, Tonn JC (2011) Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer Journal international du cancer 129(3):659–670. doi: 10.1002/ijc.26083 PubMedCrossRefGoogle Scholar
  106. 106.
    Maxwell JA, Johnson SP, McLendon RE, Lister DW, Horne KS, Rasheed A, Quinn JA, Ali-Osman F, Friedman AH, Modrich PL, Bigner DD, Friedman HS (2008) Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma. Clin Cancer Res 14(15):4859–4868. doi: 10.1158/1078-0432.ccr-07-4807 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Stark AM, Doukas A, Hugo HH, Hedderich J, Hattermann K, Maximilian Mehdorn H, Held-Feindt J (2015) Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma. Neurol Res 37(2):95–105. doi: 10.1179/1743132814y.0000000409 PubMedCrossRefGoogle Scholar
  108. 108.
    Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, O’Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Richardson D, Shepherd R, Small A, Solomon H, Tofts C, Varian J, West S, Widaa S, Yates A, Easton DF, Riggins G, Roy JE, Levine KK, Mueller W, Batchelor TT, Louis DN, Stratton MR, Futreal PA, Wooster R (2006) A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 66(8):3987–3991. doi: 10.1158/0008-5472.can-06-0127 PubMedCrossRefGoogle Scholar
  109. 109.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. doi: 10.1038/nature07385 CrossRefGoogle Scholar
  110. 110.
    van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmstrom A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers ML, Saito N, Aburatani H, Mukasa A, Berger MS, Soderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF (2015) Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 129(4):597–607. doi: 10.1007/s00401-015-1403-6 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Cure Brain Cancer Foundation Biomarkers and Translational Research, Adult Cancer Program, Lowy Cancer Research CentreUniversity of New South WalesSydneyAustralia

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