Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia
Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immuni...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/6/1829 |
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| author | Shawn H. R. Lee Zhenhua Li Evelyn H. Z. Lim Winnie H. N. Chin Nan Jiang Kean Hui Chiew Zhiwei Chen Bernice L. Z. Oh Ah Moy Tan Hany Ariffin Jun J. Yang Allen E. J. Yeoh |
| author_facet | Shawn H. R. Lee Zhenhua Li Evelyn H. Z. Lim Winnie H. N. Chin Nan Jiang Kean Hui Chiew Zhiwei Chen Bernice L. Z. Oh Ah Moy Tan Hany Ariffin Jun J. Yang Allen E. J. Yeoh |
| author_sort | Shawn H. R. Lee |
| collection | DOAJ |
| description | Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL. |
| first_indexed | 2024-03-11T06:48:21Z |
| format | Article |
| id | doaj.art-1fe421c605494c93bd4d136def72450c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T06:48:21Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1fe421c605494c93bd4d136def72450c2023-11-17T10:07:46ZengMDPI AGCancers2072-66942023-03-01156182910.3390/cancers15061829Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic LeukemiaShawn H. R. Lee0Zhenhua Li1Evelyn H. Z. Lim2Winnie H. N. Chin3Nan Jiang4Kean Hui Chiew5Zhiwei Chen6Bernice L. Z. Oh7Ah Moy Tan8Hany Ariffin9Jun J. Yang10Allen E. J. Yeoh11Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeDepartment of Pediatrics, KK Women and Children’s Hospital, Singapore 229899, SingaporeDepartment of Pediatrics, University of Malaya Medical Centre, Kuala Lumpur 59100, MalaysiaDepartment of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Lower Kent Ridge Road, Tower Block Level 12, Singapore 119228, SingaporeAsparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL.https://www.mdpi.com/2072-6694/15/6/1829T-cell receptor repertoireL-asparaginaseallergyhypersensitivitychildhood acute lymphoblastic leukemia |
| spellingShingle | Shawn H. R. Lee Zhenhua Li Evelyn H. Z. Lim Winnie H. N. Chin Nan Jiang Kean Hui Chiew Zhiwei Chen Bernice L. Z. Oh Ah Moy Tan Hany Ariffin Jun J. Yang Allen E. J. Yeoh Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia Cancers T-cell receptor repertoire L-asparaginase allergy hypersensitivity childhood acute lymphoblastic leukemia |
| title | Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia |
| title_full | Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia |
| title_fullStr | Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia |
| title_full_unstemmed | Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia |
| title_short | Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia |
| title_sort | associations of t cell receptor repertoire diversity with l asparaginase allergy in childhood acute lymphoblastic leukemia |
| topic | T-cell receptor repertoire L-asparaginase allergy hypersensitivity childhood acute lymphoblastic leukemia |
| url | https://www.mdpi.com/2072-6694/15/6/1829 |
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