Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro
Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineag...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/8/e002352.full |
| _version_ | 1818826334298701824 |
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| author | Veronika Mancikova Helena Peschelova Veronika Kozlova Aneta Ledererova Adriana Ladungova Jan Verner Tomas Loja Sarka Pospisilova Michal Smida Lenka Dostalova Martin Culen |
| author_facet | Veronika Mancikova Helena Peschelova Veronika Kozlova Aneta Ledererova Adriana Ladungova Jan Verner Tomas Loja Sarka Pospisilova Michal Smida Lenka Dostalova Martin Culen |
| author_sort | Veronika Mancikova |
| collection | DOAJ |
| description | Background Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse.Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD-scid IL2Rgnull mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells.Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments.Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors. |
| first_indexed | 2024-12-19T00:26:00Z |
| format | Article |
| id | doaj.art-6bcdb3d13e154c7d93d622142968214e |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T00:26:00Z |
| publishDate | 2021-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-6bcdb3d13e154c7d93d622142968214e2022-12-21T20:45:15ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-08-019810.1136/jitc-2021-002352Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitroVeronika Mancikova0Helena Peschelova1Veronika Kozlova2Aneta Ledererova3Adriana Ladungova4Jan Verner5Tomas Loja6Sarka Pospisilova7Michal Smida8Lenka Dostalova9Martin Culen10Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology (CEITEC), Masaryk University, Brno, Czech RepublicCentral European Institute of Technology, Masaryk University, Brno, Czech RepublicCentral European Institute of Technology, Masaryk University, Brno, Czech RepublicBackground Anti-CD19 chimeric antigen receptor T cells (CART-19) frequently induce remissions in hemato-oncological patients with recurred and/or refractory B-cell tumors. However, malignant cells sometimes escape the immunotherapeutic targeting by CD19 gene mutations, alternative splicing or lineage switch, commonly causing lack of CD19 expression on the surface of neoplastic cells. We assumed that, in addition to the known mechanisms, other means could act on CD19 to drive antigen-negative relapse.Methods Herein, we studied the mechanism of antigen loss in an in vivo CD19-negative recurrence model of chronic lymphocytic leukemia (CLL) to CART-19, established using NOD-scid IL2Rgnull mice and HG3 cell line. We validated our findings in vitro in immortalized B-cell lines and primary CLL cells.Results In our in vivo CLL recurrence model, up to 70% of CART-19-treated mice eventually recurred with CD19-negative disease weeks after initial positive response. We found that the lack of CD19 expression was caused by promoter DNA hypermethylation. Importantly, the expression loss was partially reversible by treatment with a demethylating agent. Moreover, this escape mechanism was common for 3 B-cell immortalized lines as well as primary CLL cells, as assessed by in vitro coculture experiments.Conclusions Epigenetically driven antigen escape could represent a novel, yet at least partially reversible, means of CD19 loss to CART-19 in B-cell tumors.https://jitc.bmj.com/content/9/8/e002352.full |
| spellingShingle | Veronika Mancikova Helena Peschelova Veronika Kozlova Aneta Ledererova Adriana Ladungova Jan Verner Tomas Loja Sarka Pospisilova Michal Smida Lenka Dostalova Martin Culen Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro Journal for ImmunoTherapy of Cancer |
| title | Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro |
| title_full | Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro |
| title_fullStr | Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro |
| title_full_unstemmed | Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro |
| title_short | Hypermethylation of CD19 promoter enables antigen-negative escape to CART-19 in vivo and in vitro |
| title_sort | hypermethylation of cd19 promoter enables antigen negative escape to cart 19 in vivo and in vitro |
| url | https://jitc.bmj.com/content/9/8/e002352.full |
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