Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma

Science Translational Medicine

Volumn 8, Issue 328, 2016, Pages

  Garg, Abhishek D ^a   Vandenberk, Lien ^a   Koks, Carolien ^a   Verschuere, Tina ^b   Boon, Louis ^c   Van Gool, Stefaan W ^a   Agostinis, Patrizia ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b KU LEUVEN UNIVERSITY OF LEUVEN   (Belgium)

^c EPIRUS Biopharmaceuticals Netherlands BV   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

DENDRITIC CELL VACCINE; HYPERICIN; MYELOID DIFFERENTIATION FACTOR 88; REACTIVE OXYGEN METABOLITE; TEMOZOLOMIDE; CANCER VACCINE; PERYLENE;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CELL DEATH; CONTROLLED STUDY; CYTOTOXIC T LYMPHOCYTE; DRUG POTENTIATION; GLIOMA; HUMAN; IMMUNOGENIC CELL DEATH; IMMUNOGENICITY; IMMUNOSTIMULATION; MOUSE; NONHUMAN; PHOTODYNAMIC THERAPY; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; SURVIVAL; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TUMOR REJECTION; ANALOGS AND DERIVATIVES; ANIMAL; APOPTOSIS; BRAIN TUMOR; C57BL MOUSE; CANCER GRADING; CD8+ T LYMPHOCYTE; DENDRITIC CELL; DRUG EFFECTS; ENDOPLASMIC RETICULUM STRESS; IMMUNOLOGY; METABOLISM; PATHOLOGY; PHOTOCHEMOTHERAPY;

ADAPTIVE IMMUNITY; ANIMALS; APOPTOSIS; BRAIN NEOPLASMS; CANCER VACCINES; CD8-POSITIVE T-LYMPHOCYTES; CELL DEATH; DENDRITIC CELLS; ENDOPLASMIC RETICULUM STRESS; GLIOMA; MICE; MICE, INBRED C57BL; NEOPLASM GRADING; PERYLENE; PHOTOCHEMOTHERAPY; REACTIVE OXYGEN SPECIES; T-LYMPHOCYTES, CYTOTOXIC;

EID: 84959452716     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aae0105     Document Type: Article

References (82)

1. K. Palucka, J. Banchereau, Dendritic-cell-based therapeutic cancer vaccines. Immunity 39, 38-48 (2013).
2. A. M. Dudek, S. Martin, A. D. Garg, P. Agostinis, Immature, semi-mature, and fully mature dendritic cells: Toward a DC-cancer cells interface that augments anticancer immunity. Front. Immunol. 4, 438 (2013).
3. S. Anguille, E. L. Smits, E. Lion, V. F. Van Tendeloo, Z. N. Berneman, Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15, e257-e267 (2014).
4. J.-X. Cao, X.-Y. Zhang, J.-L. Liu, D. Li, J.-L. Li, Y.-S. Liu, M. Wang, B.-L. Xu, H.-B. Wang, Z.-X. Wang, Clinical efficacy of tumor antigen-pulsed DC treatment for high-grade glioma patients: Evidence from a meta-analysis. PLOS One 9, e107173 (2014).
5. S. Polyzoidis, J. Tuazon, L. Brazil, R. Beaney, S. T. Al-Sarraj, L. Doey, J. Logan, V. Hurwitz, J. Jarosz, R. Bhangoo, R. Gullan, A. Mijovic, M. Richardson, F. Farzaneh, K. Ashkan, Active dendritic cell immunotherapy for glioblastoma: Current status and challenges. Br. J. Neurosurg. 29, 197-205 (2015).
6. R. Stupp, M. E. Hegi, W. P. Mason, M. J. Van Den Bent, M. J. B. Taphoorn, R. C. Janzer, S. K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. A. Brandes, J. Gijtenbeek, C. Marosi, C. J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J. G. Cairncross, R. O. Mirimanoff; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group, 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. 10, 459-466 (2009).
7. Q. Xie, S. Mittal, M. E. Berens, Targeting adaptive glioblastoma: An overview of proliferation and invasion. Neuro Oncol. 16, 1575-1584 (2014).
8. M. Dey, A. L. Chang, J. Miska, D. A. Wainwright, A. U. Ahmed, I. V. Balyasnikova, P. Pytel, Y. Han, A. Tobias, L. Zhang, J. Qiao, M. S. Lesniak, Dendritic cell-based vaccines that utilize myeloid rather than plasmacytoid cells offer a superior survival advantage in malignant glioma. J. Immunol. 195, 367-376 (2015).
9. C.-H. Kim, S.-J. Woo, J.-S. Park, H.-S. Kim, M.-Y. Park, S.-D. Park, Y.-K. Hong, T.-G. Kim, Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma. Immunology 122, 615-622 (2007).
10. C. E. Fadul, J. L. Fisher, T. H. Hampton, E. C. Lallana, Z. Li, J. Gui, Z. M. Szczepiorkowski, T. D. Tosteson, C. H. Rhodes, H. A. Wishart, L. D. Lewis, M. S. Ernstoff, Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J. Immunother. 34, 382-389 (2011).
11. M. K. Hunn, E. Bauer, C. E. Wood, O. Gasser, M. Dzhelali, L. R. Ancelet, B. Mester, K. J. Sharples, M. P. Findlay, D. A. Hamilton, I. F. Hermans, Dendritic cell vaccination combined with temozolomide retreatment: Results of a phase I trial in patients with recurrent glioblastoma multiforme. J. Neurooncol. 121, 319-329 (2015).
12. S. Van Gool, W. Maes, H. Ardon, T. Verschuere, S. Van Cauter, S. De Vleeschouwer, Dendritic cell therapy of high-grade gliomas. Brain Pathol. 19, 694-712 (2009).
13. G. Kroemer, L. Galluzzi, O. Kepp, L. Zitvogel, Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51-72 (2013).
14. A. D. Garg, L. Galluzzi, L. Apetoh, T. Baert, R. B. Birge, J. M. Bravo-San Pedro, K. Breckpot, D. Brough, R. Chaurio, M. Cirone, A. Coosemans, P. G. Coulie, D. De Ruysscher, L. Dini, P. De Witte, A. M. Dudek-Peric, A. Faggioni, J. Fucikova, U. S. Gaipl, J. Golab, M.-L. Gougeon, M. R. Hamblin, A. Hemminki, M. Herrmann, J. W. Hodge, O. Kepp, G. Kroemer, D. V. Krysko, W. G. Land, F. Madeo, A. A. Manfredi, S. R. Mattarollo, C. Maueroder, N. Merendino, G. Multhoff, T. Pabst, J.-E. Ricci, C. Riganti, E. Romano, N. Rufo, M. J. Smyth, J. r. Sonnemann, R. Spisek, J. Stagg, E. Vacchelli, P. Vandenabeele, L. Vandenberk, B. J. Van Den Eynde, S. W. Van Gool, F. Velotti, L. Zitvogel, P. Agostinis, Molecular and translational classifications of DAMPs in immunogenic cell death. Front. Immunol. 6, 588 (2015).
15. A. D. Garg, S. Martin, J. Golab, P. Agostinis, Danger signalling during cancer cell death: Origins, plasticity and regulation. Cell Death Differ. 21, 26-38 (2014).
16. A. D. Garg, D. V. Krysko, T. Verfaillie, A. Kaczmarek, G. B. Ferreira, T. Marysael, N. Rubio, M. Firczuk, C. Mathieu, A. J. M. Roebroek, W. Annaert, J. Golab, P. De Witte, P. Vandenabeele, P. Agostinis, A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31, 1062-1079 (2012).
17. A. D. Garg, S. Elsen, D. V. Krysko, P. Vandenabeele, P. De Witte, P. Agostinis, Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal. Oncotarget 6, 26841-26860 (2015).
18. A. D. Garg, A. M. Dudek, G. B. Ferreira, T. Verfaillie, P. Vandenabeele, D. V. Krysko, C. Mathieu, P. Agostinis, ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy 9, 1292-1307 (2013).
19. A. M. Dudek-Peric, G. B. Ferreira, A. Muchowicz, J. Wouters, N. Prada, S. Martin, S. Kiviluoto, M. Winiarska, L. Boon, C. Mathieu, J. Van Den Oord, M. Stas, M.-L. Gougeon, J. Golab, A. D. Garg, P. Agostinis, Antitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin. Cancer Res. 75, 1603-1614 (2015).
20. D. Kacerovská, K. Pizinger, F. Majer, F. Šmid, Photodynamic therapy of nonmelanoma skin cancer with topical Hypericum perforatum extract-A pilot study. Photochem. Photobiol. 84, 779-785 (2008).
21. A. H. Rook, G. S. Wood, M. Duvic, E. C. Vonderheid, A. Tobia, B. Cabana, A phase II placebocontrolled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J. Am. Acad. Dermatol. 63, 984-990 (2010).
22. M. Alecu, C. Ursaciuc, F. Halalau, G. Coman, W. Merlevede, E. Waelkens, P. De Witte, Photodynamic treatment of basal cell carcinoma and squamous cell carcinoma with hypericin. Anticancer Res 18, 4651-4654 (1998).
23. C. A. Koks, A. D. Garg, M. Ehrhardt, M. Riva, L. Vandenberk, L. Boon, S. De Vleeschouwer, P. Agostinis, N. Graf, S. W. Van Gool, Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death. Int. J. Cancer 136, E313-E325 (2015).
24. M. Eyrich, S. C. Schreiber, J. Rachor, J. Krauss, F. Pauwels, J. Hain, M. Wölfl, M. B. Lutz, S. De Vleeschouwer, P. G. Schlegel, S. W. Van Gool, Development and validation of a fully GMPcompliant production process of autologous, tumor-lysate-pulsed dendritic cells. Cytotherapy 16, 946-964 (2014).
25. L. Vandenberk, A. D. Garg, T. Verschuere, C. Koks, J. Belmans, M. Beullens, P. Agostinis, S. De Vleeschouwer, S. Van Gool, Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology 10.1080/2162402X.2015.1083669 (2015).
26. W. Stummer, F. Rodrigues, P. Schucht, M. Preuss, D. Wiewrodt, U. Nestler, M. Stein, J. M. C. Artero, N. Platania, J. Skjoth-Rasmussen, A. Della Puppa, J. Caird, S. Cortnum, S. Eljamel, C. Ewald, L. González-García, A. J. Martin, A. Melada, A. Peraud, A. Brentrup, T. Santarius, H. H. Steiner; European ALA Pediatric Brain Tumor Study Group, Predicting the "usefulness" of 5-ALAderived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: A European survey. Acta Neurochir. 156, 2315-2324 (2014).
27. W.Maes, G. G. Rosas, B. Verbinnen, L. Boon, S. De Vleeschouwer, J. L. Ceuppens, S.W. Van Gool, DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma. Neuro Oncol. 11, 529-542 (2009).
28. T. Doucette, G. Rao, A. Rao, L. Shen, K. Aldape, J. Wei, K. Dziurzynski, M. Gilbert, A. B. Heimberger, Immune heterogeneity of glioblastoma subtypes: Extrapolation from the cancer genome atlas. Cancer Immunol. Res. 1, 112-122 (2013).
29. T. Oh, S. Fakurnejad, E. T. Sayegh, A. J. Clark, M. E. Ivan, M. Z. Sun, M. Safaee, O. Bloch, C. D. James, A. T. Parsa, Immunocompetent murine models for the study of glioblastoma immunotherapy. J. Transl. Med. 12, 107 (2014).
30. L. Apetoh, F. Ghiringhelli, A. Tesniere, M. Obeid, C. Ortiz, A. Criollo, G. Mignot, M. C. Maiuri, E. Ullrich, P. Saulnier, H. Yang, S. Amigorena, B. Ryffel, F. J. Barrat, P. Saftig, F. Levi, R. Lidereau, C. Nogues, J.-P. Mira, A. Chompret, V. Joulin, F. Clavel-Chapelon, J. Bourhis, F. André, S. Delaloge, T. Tursz, G. Kroemer, L. Zitvogel, Toll-like receptor 4-dependent contribution of the immune systemto anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050-1059 (2007).
31. N. Warner, G. Núñez, MyD88: A critical adaptor protein in innate immunity signal transduction. J. Immunol. 190, 3-4 (2013).
32. M. Ciampricotti, C.-S. Hau, C. W. Doornebal, J. Jonkers, K. E. De Visser, Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat. Med. 18, 344-346 (2012).
33. R. Clarke, Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models. Breast Cancer Res. Treat. 46, 255-278 (1997).
34. S. Sengupta, J. Marrinan, C. Frishman, P. Sampath, Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin. Dev. Immunol. 2012, 831090 (2012).
35. W. H. Fridman, F. Pagès, C. Sautès-Fridman, J. Galon, The immune contexture in human tumours: Impact on clinical outcome. Nat. Rev. Cancer 12, 298-306 (2012).
36. H. Angell, J. Galon, From the immune contexture to the Immunoscore: The role of prognostic and predictive immune markers in cancer. Curr. Opin. Immunol. 25, 261-267 (2013).
37. G. Bindea, B. Mlecnik, M. Tosolini, A. Kirilovsky, M. Waldner, A. C. Obenauf, H. Angell, T. Fredriksen, L. Lafontaine, A. Berger, P. Bruneval, W. H. Fridman, C. Becker, F. Pagès, M. R. Speicher, Z. Trajanoski, J. Galon, Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782-795 (2013).
38. A. J. Gentles, A. M. Newman, C. L. Liu, S. V. Bratman, W. Feng, D. Kim, V. S. Nair, Y. Xu, A. Khuong, C. D. Hoang, M. Diehn, R. B. West, S. K. Plevritis, A. A. Alizadeh, The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938-945 (2015).
39. C. W. Brennan, R. G. W. Verhaak, A. McKenna, B. Campos, H. Noushmehr, S. R. Salama, S. Zheng, D. Chakravarty, J. Z. Sanborn, S. H. Berman, R. Beroukhim, B. Bernard, C.-J. Wu, G. Genovese, I. Shmulevich, J. Barnholtz-Sloan, L. Zou, R. Vegesna, S. A. Shukla, G. Ciriello, W. K. Yung, W. Zhang, C. Sougnez, T. Mikkelsen, K. Aldape, D. D. Bigner, E. G. Van Meir, M. Prados, A. Sloan, K. L. Black, J. Eschbacher, G. Finocchiaro, W. Friedman, D. W. Andrews, A. Guha, M. Iacocca, B. P. O'Neill, G. Foltz, J. Myers, D. J. Weisenberger, R. Penny, R. Kucherlapati, C. M. Perou, D. N. Hayes, R. Gibbs, M. Marra, G. B. Mills, E. Lander, P. Spellman, R. Wilson, C. Sander, J. Weinstein, M. Meyerson, S. Gabriel, P. W. Laird, D. Haussler, G. Getz, L. Chin; TCGA Research Network, The somatic genomic landscape of glioblastoma. Cell 155, 462-477 (2013).
40. The Cancer Genome Atlas Research Network, Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068 (2008).
41. A. D. Garg, D. De Ruysscher, P. Agostinis, Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis. Oncoimmunology 10.1080/2162402X.2015.1069938 (2015).
42. H.-M. Chen, P.-H. Wang, S.-S. Chen, C.-C. Wen, Y.-H. Chen, W.-C. Yang, N.-S. Yang, Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol. Immunother. 61, 1989-2002 (2012).
43. T.-J. Lin, H.-T. Lin, W.-T. Chang, S. P. Mitapalli, P.-W. Hsiao, S.-Y. Yin, N.-S. Yang, Shikoninenhanced cell immunogenicity of tumor vaccine is mediated by the differential effects of DAMP components. Mol. Cancer 14, 174 (2015).
44. I. Vogel, B. Verbinnen, W. Maes, L. Boon, S. W. Van Gool, J. L. Ceuppens, Foxp3+ regulatory T cells are activated in spite of B7-CD28 and CD40-CD40L blockade. Eur. J. Immunol. 43, 1013-1023 (2013).
45. R. Ritz, R. Daniels, S. Noell, G. C. Feigl, V. Schmidt, A. Bornemann, K. Ramina, D. Mayer, K. Dietz, W. S. L. Strauss, M. Tatagiba, Hypericin for visualization of high grade gliomas: First clinical experience. Eur. J Surg. Oncol. 38, 352-360 (2012).
46. J. L. Gulley, R. A. Madan, J. Schlom, Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr. Oncol. 18, e150-e157 (2011).
47. R. Ramakrishnan, D. Assudani, S. Nagaraj, T. Hunter, H.-I. Cho, S. Antonia, S. Altiok, E. Celis, D. I. Gabrilovich, Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111-1124 (2010).
48. A. B. Heimberger, W. Sun, S. F. Hussain, M. Dey, L. Crutcher, K. Aldape, M. Gilbert, S. J. Hassenbusch, R. Sawaya, B. Schmittling, G. E. Archer, D. A. Mitchell, D. D. Bigner, J. H. Sampson, Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study. Neuro Oncol. 10, 98-103 (2008).
49. T.-G. Kim, C.-H. Kim, J.-S. Park, S.-D. Park, C. K. Kim, D.-S. Chung, Y.-K. Hong, Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin. Vaccine Immunol. 17, 143-153 (2010).
50. P. G. Coulie, B. J. Van Den Eynde, P. Van der Bruggen, T. Boon, Tumour antigens recognized by T lymphocytes: At the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135-146 (2014).
51. M. Obeid, A. Tesniere, F. Ghiringhelli, G. M. Fimia, L. Apetoh, J.-L. Perfettini, M. Castedo, G. Mignot, T. Panaretakis, N. Casares, D. Métivier, N. Larochette, P. Van Endert, F. Ciccosanti, M. Piacentini, L. Zitvogel, G. Kroemer, Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54-61 (2007).
52. T. Verschuere, J. Toelen, W. Maes, F. Poirier, L. Boon, T. Tousseyn, T. Mathivet, H. Gerhardt, V. Mathieu, R. Kiss, F. Lefranc, S. W. Van Gool, S. De Vleeschouwer, Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity. Int. J. Cancer 134, 873-884 (2014).
53. A. Vantieghem, Z. Assefa, P. Vandenabeele, W. Declercq, S. Courtois, J. R. Vandenheede, W. Merlevede, P. De Witte, P. Agostinis, Hypericin-induced photosensitization of HeLa cells leads to apoptosis or necrosis. Involvement of cytochrome c and procaspase-3 activation in the mechanism of apoptosis. FEBS Lett. 440, 19-24 (1998).
54. E. Buytaert, G. Callewaert, N. Hendrickx, L. Scorrano, D. Hartmann, L. Missiaen, J. R. Vandenheede, I. Heirman, J. Grooten, P. Agostinis, Role of endoplasmic reticulum depletion and multidomain proapoptotic BAX and BAK proteins in shaping cell death after hypericin-mediated photodynamic therapy. FASEB J. 20, 756-758 (2006).
55. T. Verfaillie, N. Rubio, A. D. Garg, G. Bultynck, R. Rizzuto, J.-P. Decuypere, J. Piette, C. Linehan, S. Gupta, A. Samali, P. Agostinis, PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19, 1880-1891 (2012).
56. H. Maes, S. Van Eygen, D. V. Krysko, P. Vandenabeele, K. Nys, K. Rillaerts, A. D. Garg, T. Verfaillie, P. Agostinis, BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell Death Dis. 5, e1127 (2014).
57. I. Coupienne, S. Bontems, M. Dewaele, N. Rubio, Y. Habraken, S. Fulda, P. Agostinis, J. Piette, NF-kB inhibition improves the sensitivity of human glioblastoma cells to 5-aminolevulinic acid-based photodynamic therapy. Biochem. Pharmacol. 81, 606-616 (2011).
58. Cancer Genome Atlas Research Network, J. N.Weinstein, E. A. Collisson, G. B.Mills, K. R. Shaw, B. A. Ozenberger, K. Ellrott, I. Shmulevich, C. Sander, J. M. Stuart, The Cancer Genome Atlas pan-cancer analysis project. Nat. Genet. 45, 1113-1120 (2013).
59. E. Cerami, J. Gao, U. Dogrusoz, B. E. Gross, S. O. Sumer, B. A. Aksoy, A. Jacobsen, C. J. Byrne, M. L. Heuer, E. Larsson, Y. Antipin, B. Reva, A. P. Goldberg, C. Sander, N. Schultz, The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404 (2012).
60. M. J. L. De Hoon, S. Imoto, J. Nolan, S. Miyano, Open source clustering software. Bioinformatics 20, 1453-1454 (2004).
61. A. J. Saldanha, Java Treeview-Extensible visualization of microarray data. Bioinformatics 20, 3246-3248 (2004).
62. G. Stoll, G. Bindea, B. Mlecnik, J. Galon, L. Zitvogel, G. Kroemer, Meta-analysis of organspecific differences in the structure of the immune infiltrate in major malignancies. Oncotarget 6, 11894-11909 (2015).
63. C. P. Goswami, H. Nakshatri, PROGgeneV2: Enhancements on the existing database. BMC Cancer 14, 970 (2014).
64. E. J. Sayour, P. McLendon, R. McLendon, G. De Leon, R. Reynolds, J. Kresak, J. H. Sampson, D. A. Mitchell, Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma. Cancer Immunol. Immunother. 64, 419-427 (2015).
65. J. Kmiecik, A. Poli, N. H. C. Brons, A. Waha, G. E. Eide, P. O. Enger, J. Zimmer, M. Chekenya, 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. 264, 71-83 (2013).
66. E. T. Wong, E. Lok, S. Gautam, K. D. Swanson, Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br. J. Cancer 113, 232-241 (2015).
67. J. K. Wiencke, W. P. Accomando, S. Zheng, J. Patoka, X. Dou, J. J. Phillips, G. Hsuang, B. C. Christensen, E. A. Houseman, D. C. Koestler, P. Bracci, J. L. Wiemels, M. Wrensch, H. H. Nelson, K. T. Kelsey, Epigenetic biomarkers of T-cells in human glioma. Epigenetics 7, 1391-1402 (2012).
68. S. Han, Y. Liu, Q. Li, Z. Li, H. Hou, A. Wu, Pre-treatment neutrophil-to-lymphocyte ratio is associated with neutrophil and T-cell infiltration and predicts clinical outcome in patients with glioblastoma. BMC Cancer 15, 617 (2015).
69. A. A. Thomas, J. L. Fisher, G. J. Rahme, T. H. Hampton, U.Baron, S. Olek, T. Schwachula, C.H.Rhodes, J. Gui, L. J. Tafe, G. J. Tsongalis, J. A. Lefferts, H. Wishart, J. Kleen, M. Miller, C. A. Whipple, F. B. De Abreu, M. S. Ernstoff, C. E. Fadul, Regulatory T cells are not a strong predictor of survival for patientswith glioblastoma. Neuro Oncol. 17, 801-809 (2015).
70. A. S. Berghoff, B. Kiesel, G. Widhalm, O. Rajky, G. Ricken, A. Wöhrer, K. Dieckmann, M. Filipits, A. Brandstetter, M. Weller, S. Kurscheid, M. E. Hegi, C. C. Zielinski, C. Marosi, J. A. Hainfellner, M. Preusser, W. Wick, Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 17, 1064-1075 (2015).
71. K. Gousias, S. Voulgaris, G. Vartholomatos, P. Voulgari, A. P. Kyritsis, M. Markou, Prognostic value of the preoperative immunological profile in patients with glioblastoma. Surg. Neurol. Int. 5, 89 (2014).
72. J. Lohr, T. Ratliff, A. Huppertz, Y. Ge, C. Dictus, R. Ahmadi, S. Grau, N. Hiraoka, V. Eckstein, R. C. Ecker, T. Korff, A. Von Deimling, A. Unterberg, P. Beckhove, C. Herold-Mende, Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-b. Clin. Cancer Res. 17, 4296-4308 (2011).
73. S. A. Grossman, X. Ye, G. Lesser, A. Sloan, H. Carraway, S. Desideri, S. Piantadosi; NABTT CNS Consortium, Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin. Cancer Res. 17, 5473-5480 (2011).
74. S. Han, C. Zhang, Q. Li, J. Dong, Y. Liu, Y. Huang, T. Jiang, A. Wu, Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma. Br. J. Cancer 110, 2560-2568 (2014).
75. Y.-H. Kim, T.-Y. Jung, S. Jung, W.-Y. Jang, K.-S. Moon, I.-Y. Kim, M.-C. Lee, J.-J. Lee, Tumourinfiltrating T-cell subpopulations in glioblastomas. Br. J. Neurosurg. 26, 21-27 (2012).
76. I. Yang, T. Tihan, S. J. Han, M. R. Wrensch, J. Wiencke, M. E. Sughrue, A. T. Parsa, CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J. Clin. Neurosci. 17, 1381-1385 (2010).
77. Q. Yue, X. Zhang, H.-x. Ye, Y. Wang, Z.-g. Du, Y. Yao, Y. Mao, The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma. J. Neurooncol. 116, 251-259 (2014).
78. A. El Andaloussi, M. S. Lesniak, CD4+ CD25+ FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J. Neurooncol. 83, 145-152 (2007).
79. J. F. M. Jacobs, A. J. Idema, K. F. Bol, J. A. Grotenhuis, I. J. De Vries, P. Wesseling, G. J. Adema, Prognostic significance and mechanism of Treg infiltration in human brain tumors. J. Neuroimmunol. 225, 195-199 (2010).
80. A. B. Heimberger, M. Abou-Ghazal, C. Reina-Ortiz, D. S. Yang, W. Sun, W. Qiao, N. Hiraoka, G. N. Fuller, Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin. Cancer Res. 14, 5166-5172 (2008).
81. B. Fong, R. Jin, X. Wang, M. Safaee, D. N. Lisiero, I. Yang, G. Li, L. M. Liau, R. M. Prins, Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLOS One 7, e32614 (2012).
82. X. Cui, Z. Xu, Z. Zhao, D. Sui, X. Ren, Q. Huang, J. Qin, L. Hao, Z. Wang, L. Shen, S. Lin, Analysis of CD137L and IL-17 expression in tumor tissue as prognostic indicators for gliblastoma. Int. J. Biol. Sci. 9, 134-141 (2013).