Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-06-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/6/200 |
| _version_ | 1797706586568785920 |
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| author | Antoni Xavier Torres-Collado Ali R. Jazirehi |
| author_facet | Antoni Xavier Torres-Collado Ali R. Jazirehi |
| author_sort | Antoni Xavier Torres-Collado |
| collection | DOAJ |
| description | Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8+ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19+ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL. |
| first_indexed | 2024-03-12T05:53:30Z |
| format | Article |
| id | doaj.art-6c30a3743c204e81840abc84af3a0091 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T05:53:30Z |
| publishDate | 2018-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6c30a3743c204e81840abc84af3a00912023-09-03T04:52:57ZengMDPI AGCancers2072-66942018-06-0110620010.3390/cancers10060200cancers10060200Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase InhibitorsAntoni Xavier Torres-Collado0Ali R. Jazirehi1Department of Surgery, Division of Surgical Oncology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USADepartment of Surgery, Division of Surgical Oncology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USAPatients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8+ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19+ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL.http://www.mdpi.com/2072-6694/10/6/200chimeric antigen receptornon-Hodgkin’s lymphomaadoptive cell transferapoptosissignal transductionimmunotherapyresistanceB cell hematological malignanciesCelebrexhistone deacetylase inhibitor |
| spellingShingle | Antoni Xavier Torres-Collado Ali R. Jazirehi Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors Cancers chimeric antigen receptor non-Hodgkin’s lymphoma adoptive cell transfer apoptosis signal transduction immunotherapy resistance B cell hematological malignancies Celebrex histone deacetylase inhibitor |
| title | Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors |
| title_full | Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors |
| title_fullStr | Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors |
| title_full_unstemmed | Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors |
| title_short | Overcoming Resistance of Human Non-Hodgkin’s Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors |
| title_sort | overcoming resistance of human non hodgkin s lymphoma to cd19 car ctl therapy by celecoxib and histone deacetylase inhibitors |
| topic | chimeric antigen receptor non-Hodgkin’s lymphoma adoptive cell transfer apoptosis signal transduction immunotherapy resistance B cell hematological malignancies Celebrex histone deacetylase inhibitor |
| url | http://www.mdpi.com/2072-6694/10/6/200 |
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