TRIGGERING THE TCR DEVELOPMENTAL CHECKPOINT ACTIVATES A THERAPEUTICALLY TARGETABLE TUMOR SUPPRESSIVE PATHWAY IN T-CELL LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Trinquand A. 06/12/16; 135293; S799
Dr. Amélie Trinquand
Contributions
Contributions
Abstract
Abstract: S799
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C11
Background
T-cell acute lymphoblastic leukemia (T-ALL) results from the leukemic transformation of thymic cell precursors caused by a multistep pathogenesis involving numerous genetic and epigenetic abnormalities. They are characterized by high relapse rates and poor prognosis, calling for the search of novel therapeutic options. T lymphocytes differentiate in the thymus according to a highly orchestrated process involving developmental checkpoints. Among these, negative selection is a major process by which thymocytes recognizing self-Major Histocompatibility complex with high affinity are eliminated by TCR-mediated apoptosis.
Aims
In this study, we hypothesized that tissue homeostatic regulators may be amenable to reactivation in tumor cells. We inferred that experimentally chronic/persistent induced TCR signaling in T-ALL could initiate a molecular program similar to negative selection of thymic T-cell progenitors and induce cell death.
Methods
We used the transgenic Marilyn TCR-HY in a human T-ALL cell line (ALL-SIL) and in a mouse model of TEL-JAK2-induced T-ALL, to test TCR activation by its cognate peptide/MHC. We evaluated chronic/persistent TCR activation by anti-CD3ε monoclonal antibody in vitro (in TCR-HY ALL-SIL and in a panel of 36 primary T-ALL patients cases) and in vivo (in TJK2/CD3ε+ and TJK2/CD3ε- mouse T-ALL model and in xenotransplanted mice with 7 human T-ALL).
Results
Using the Marilyn TCR-HY transgene, we showed that TCR activation by its cognate peptide/MHC induced apoptosis in vitro (ALL-SIL TLX+ cell line) and dramatically impaired development/maintenance of leukemias in vivo (murine TEL-JAK2-induced T-ALL) exclusively in DBY-expressing male mice. Anti-CD3ε monoclonal antibody stimulation mimicked high affinity self-peptide/MHC-induced TCR signaling (human OKT3; murine, 145-2C11): this led to massive leukemic cell death and remarkably induced a gene expression program similar to thymic negative selection. In addition, in vitro stimulation of CD3/TCR complex with an anti-CD3ε antibody resulted in cell death of primary CD3/TCR-expressing T-ALL (n = 36) regardless their underlying oncogenetic characteristics. Keeping with this, in vivo treatment by anti-CD3ε monoclonal antibody prevented from the emergence of the leukemic process in several TCR+ T-ALL murine models, whereas it had virtually no impact on the survival of mice engrafted with murine CD3ε-/- T-ALL cells. Importantly, anti-CD3ε treatment hampered leukemogenesis in xenotransplanted mice with human TCR/CD3+ T-ALL (n = 7) in both preventative and curative settings.
Conclusion
In our study, we found that reactivation in T-ALL blasts of the lineage-specific checkpoint control normally set by TCR signaling during T-cell development, displays anti-tumoral functions. Importantly, despite the multiple and complex oncogenic mechanisms driving T-ALL, this TCR-dependent checkpoint remains switchable to induce massive tumor cell apoptosis. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.
Session topic: ALL Biology - Transcriptional dysregulation
Keyword(s): T-ALL, TCR
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C11
Background
T-cell acute lymphoblastic leukemia (T-ALL) results from the leukemic transformation of thymic cell precursors caused by a multistep pathogenesis involving numerous genetic and epigenetic abnormalities. They are characterized by high relapse rates and poor prognosis, calling for the search of novel therapeutic options. T lymphocytes differentiate in the thymus according to a highly orchestrated process involving developmental checkpoints. Among these, negative selection is a major process by which thymocytes recognizing self-Major Histocompatibility complex with high affinity are eliminated by TCR-mediated apoptosis.
Aims
In this study, we hypothesized that tissue homeostatic regulators may be amenable to reactivation in tumor cells. We inferred that experimentally chronic/persistent induced TCR signaling in T-ALL could initiate a molecular program similar to negative selection of thymic T-cell progenitors and induce cell death.
Methods
We used the transgenic Marilyn TCR-HY in a human T-ALL cell line (ALL-SIL) and in a mouse model of TEL-JAK2-induced T-ALL, to test TCR activation by its cognate peptide/MHC. We evaluated chronic/persistent TCR activation by anti-CD3ε monoclonal antibody in vitro (in TCR-HY ALL-SIL and in a panel of 36 primary T-ALL patients cases) and in vivo (in TJK2/CD3ε+ and TJK2/CD3ε- mouse T-ALL model and in xenotransplanted mice with 7 human T-ALL).
Results
Using the Marilyn TCR-HY transgene, we showed that TCR activation by its cognate peptide/MHC induced apoptosis in vitro (ALL-SIL TLX+ cell line) and dramatically impaired development/maintenance of leukemias in vivo (murine TEL-JAK2-induced T-ALL) exclusively in DBY-expressing male mice. Anti-CD3ε monoclonal antibody stimulation mimicked high affinity self-peptide/MHC-induced TCR signaling (human OKT3; murine, 145-2C11): this led to massive leukemic cell death and remarkably induced a gene expression program similar to thymic negative selection. In addition, in vitro stimulation of CD3/TCR complex with an anti-CD3ε antibody resulted in cell death of primary CD3/TCR-expressing T-ALL (n = 36) regardless their underlying oncogenetic characteristics. Keeping with this, in vivo treatment by anti-CD3ε monoclonal antibody prevented from the emergence of the leukemic process in several TCR+ T-ALL murine models, whereas it had virtually no impact on the survival of mice engrafted with murine CD3ε-/- T-ALL cells. Importantly, anti-CD3ε treatment hampered leukemogenesis in xenotransplanted mice with human TCR/CD3+ T-ALL (n = 7) in both preventative and curative settings.
Conclusion
In our study, we found that reactivation in T-ALL blasts of the lineage-specific checkpoint control normally set by TCR signaling during T-cell development, displays anti-tumoral functions. Importantly, despite the multiple and complex oncogenic mechanisms driving T-ALL, this TCR-dependent checkpoint remains switchable to induce massive tumor cell apoptosis. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.
Session topic: ALL Biology - Transcriptional dysregulation
Keyword(s): T-ALL, TCR
Abstract: S799
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C11
Background
T-cell acute lymphoblastic leukemia (T-ALL) results from the leukemic transformation of thymic cell precursors caused by a multistep pathogenesis involving numerous genetic and epigenetic abnormalities. They are characterized by high relapse rates and poor prognosis, calling for the search of novel therapeutic options. T lymphocytes differentiate in the thymus according to a highly orchestrated process involving developmental checkpoints. Among these, negative selection is a major process by which thymocytes recognizing self-Major Histocompatibility complex with high affinity are eliminated by TCR-mediated apoptosis.
Aims
In this study, we hypothesized that tissue homeostatic regulators may be amenable to reactivation in tumor cells. We inferred that experimentally chronic/persistent induced TCR signaling in T-ALL could initiate a molecular program similar to negative selection of thymic T-cell progenitors and induce cell death.
Methods
We used the transgenic Marilyn TCR-HY in a human T-ALL cell line (ALL-SIL) and in a mouse model of TEL-JAK2-induced T-ALL, to test TCR activation by its cognate peptide/MHC. We evaluated chronic/persistent TCR activation by anti-CD3ε monoclonal antibody in vitro (in TCR-HY ALL-SIL and in a panel of 36 primary T-ALL patients cases) and in vivo (in TJK2/CD3ε+ and TJK2/CD3ε- mouse T-ALL model and in xenotransplanted mice with 7 human T-ALL).
Results
Using the Marilyn TCR-HY transgene, we showed that TCR activation by its cognate peptide/MHC induced apoptosis in vitro (ALL-SIL TLX+ cell line) and dramatically impaired development/maintenance of leukemias in vivo (murine TEL-JAK2-induced T-ALL) exclusively in DBY-expressing male mice. Anti-CD3ε monoclonal antibody stimulation mimicked high affinity self-peptide/MHC-induced TCR signaling (human OKT3; murine, 145-2C11): this led to massive leukemic cell death and remarkably induced a gene expression program similar to thymic negative selection. In addition, in vitro stimulation of CD3/TCR complex with an anti-CD3ε antibody resulted in cell death of primary CD3/TCR-expressing T-ALL (n = 36) regardless their underlying oncogenetic characteristics. Keeping with this, in vivo treatment by anti-CD3ε monoclonal antibody prevented from the emergence of the leukemic process in several TCR+ T-ALL murine models, whereas it had virtually no impact on the survival of mice engrafted with murine CD3ε-/- T-ALL cells. Importantly, anti-CD3ε treatment hampered leukemogenesis in xenotransplanted mice with human TCR/CD3+ T-ALL (n = 7) in both preventative and curative settings.
Conclusion
In our study, we found that reactivation in T-ALL blasts of the lineage-specific checkpoint control normally set by TCR signaling during T-cell development, displays anti-tumoral functions. Importantly, despite the multiple and complex oncogenic mechanisms driving T-ALL, this TCR-dependent checkpoint remains switchable to induce massive tumor cell apoptosis. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.
Session topic: ALL Biology - Transcriptional dysregulation
Keyword(s): T-ALL, TCR
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C11
Background
T-cell acute lymphoblastic leukemia (T-ALL) results from the leukemic transformation of thymic cell precursors caused by a multistep pathogenesis involving numerous genetic and epigenetic abnormalities. They are characterized by high relapse rates and poor prognosis, calling for the search of novel therapeutic options. T lymphocytes differentiate in the thymus according to a highly orchestrated process involving developmental checkpoints. Among these, negative selection is a major process by which thymocytes recognizing self-Major Histocompatibility complex with high affinity are eliminated by TCR-mediated apoptosis.
Aims
In this study, we hypothesized that tissue homeostatic regulators may be amenable to reactivation in tumor cells. We inferred that experimentally chronic/persistent induced TCR signaling in T-ALL could initiate a molecular program similar to negative selection of thymic T-cell progenitors and induce cell death.
Methods
We used the transgenic Marilyn TCR-HY in a human T-ALL cell line (ALL-SIL) and in a mouse model of TEL-JAK2-induced T-ALL, to test TCR activation by its cognate peptide/MHC. We evaluated chronic/persistent TCR activation by anti-CD3ε monoclonal antibody in vitro (in TCR-HY ALL-SIL and in a panel of 36 primary T-ALL patients cases) and in vivo (in TJK2/CD3ε+ and TJK2/CD3ε- mouse T-ALL model and in xenotransplanted mice with 7 human T-ALL).
Results
Using the Marilyn TCR-HY transgene, we showed that TCR activation by its cognate peptide/MHC induced apoptosis in vitro (ALL-SIL TLX+ cell line) and dramatically impaired development/maintenance of leukemias in vivo (murine TEL-JAK2-induced T-ALL) exclusively in DBY-expressing male mice. Anti-CD3ε monoclonal antibody stimulation mimicked high affinity self-peptide/MHC-induced TCR signaling (human OKT3; murine, 145-2C11): this led to massive leukemic cell death and remarkably induced a gene expression program similar to thymic negative selection. In addition, in vitro stimulation of CD3/TCR complex with an anti-CD3ε antibody resulted in cell death of primary CD3/TCR-expressing T-ALL (n = 36) regardless their underlying oncogenetic characteristics. Keeping with this, in vivo treatment by anti-CD3ε monoclonal antibody prevented from the emergence of the leukemic process in several TCR+ T-ALL murine models, whereas it had virtually no impact on the survival of mice engrafted with murine CD3ε-/- T-ALL cells. Importantly, anti-CD3ε treatment hampered leukemogenesis in xenotransplanted mice with human TCR/CD3+ T-ALL (n = 7) in both preventative and curative settings.
Conclusion
In our study, we found that reactivation in T-ALL blasts of the lineage-specific checkpoint control normally set by TCR signaling during T-cell development, displays anti-tumoral functions. Importantly, despite the multiple and complex oncogenic mechanisms driving T-ALL, this TCR-dependent checkpoint remains switchable to induce massive tumor cell apoptosis. These data provide a strong rationale for targeted therapy based on anti-CD3 treatment of TCR-expressing T-ALL patients and demonstrate that endogenous developmental checkpoint pathways are amenable to therapeutic intervention in cancer cells.
Session topic: ALL Biology - Transcriptional dysregulation
Keyword(s): T-ALL, TCR
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