Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells
| Autor: | Christina Dahl, Christer Lundell-Ek, Henrik J. Ditzel, Jann Mortensen, Karine N. Dzhandzhugazyan, Line Bille Madsen, Johnny Jon Fang, Helle Broholm, Walter Fischer, Morten F. Gjerstorff, Tim Lundby, Ian Law, Per Guldberg, Rikke Sick Andersen, Martin Roland Jensen, Alexei F. Kirkin, Aase Wagner |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment General Physics and Astronomy Immunotherapy Adoptive 0302 clinical medicine Cancer immunotherapy Cytotoxic T cell Prospective Studies lcsh:Science Multidisciplinary Brain Neoplasms T-Lymphocytes Helper-Inducer Antigens Neoplasm/genetics 030220 oncology & carcinogenesis Female Adult Science Antigen-Presenting Cells DNA/genetics Article General Biochemistry Genetics and Molecular Biology Young Adult 03 medical and health sciences T-Lymphocytes Helper-Inducer/immunology Antigen Antigens Neoplasm Antigen-Presenting Cells/immunology medicine Humans Antigen-presenting cell Brain Neoplasms/genetics business.industry Cancer DNA General Chemistry Immunotherapy DNA Methylation T-Lymphocytes Cytotoxic/immunology medicine.disease Glioblastoma/genetics 030104 developmental biology DNA demethylation Cancer cell Cancer research lcsh:Q Glioblastoma business T-Lymphocytes Cytotoxic |
| Zdroj: | Kirkin, A F, Dzhandzhugazyan, K N, Guldberg, P, Fang, J J, Andersen, R S, Dahl, C, Mortensen, J, Lundby, T, Wagner, A, Law, I, Broholm, H, Madsen, L, Lundell-Ek, C, Gjerstorff, M F, Ditzel, H J, Jensen, M R & Fischer, W 2018, ' Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells ', Nature Communications, vol. 9, 785 . https://doi.org/10.1038/s41467-018-03217-9 Nature Communications, Vol 9, Iss 1, Pp 1-12 (2018) Nature Communications Kirkin, A F, Dzhandzhugazyan, K N, Guldberg, P, Fang, J J, Andersen, R S, Dahl, C, Mortensen, J, Lundby, T, Wagner, A, Law, I, Broholm, H, Madsen, L, Lundell-Ek, C, Gjerstorff, M F, Ditzel, H J, Jensen, M R & Fischer, W 2018, ' Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells ', Nature Communications, vol. 9, no. 1, 785 . https://doi.org/10.1038/s41467-018-03217-9 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-03217-9 |
| Popis: | In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer. A critical determinant of tumor eradication by adoptive immunotherapy is the tumor associated antigen recognized by cytotoxic T lymphocytes. Here the authors generate ex vivo autologous cytotoxic T lymphocytes by exposure to antigens induced by DNA demethylation and report the results of a phase 1 trial of 25 patients with recurrent glioblastoma multiforme with tumor regression in three patients. |
| Databáze: | OpenAIRE |
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