T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy
Background Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not trea...
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007236.full |
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| author | Linghua Wang Siqing Fu Aung Naing Funda Meric-Bernstam Carl Morrison Joud Hajjar Mingxuan Xu Anas Alshawa Bettzy Stephen Ying Yuan Jordi Rodon Ahnert Abdulrazzak Zarifa Shrutii Sarda Timothy Looney Sapna P Patel Geoffrey M Lowman Dzifa Yawa Duose Jeffrey M Conroy Evan Kwiatkowski |
| author_facet | Linghua Wang Siqing Fu Aung Naing Funda Meric-Bernstam Carl Morrison Joud Hajjar Mingxuan Xu Anas Alshawa Bettzy Stephen Ying Yuan Jordi Rodon Ahnert Abdulrazzak Zarifa Shrutii Sarda Timothy Looney Sapna P Patel Geoffrey M Lowman Dzifa Yawa Duose Jeffrey M Conroy Evan Kwiatkowski |
| author_sort | Linghua Wang |
| collection | DOAJ |
| description | Background Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past.Patients and methods We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3).Results Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs.Conclusion The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs. |
| format | Article |
| id | doaj-art-5bcceeb01b534672b53dae6a7f264aae |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5bcceeb01b534672b53dae6a7f264aae2025-02-09T10:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007236T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapyLinghua Wang0Siqing Fu1Aung Naing2Funda Meric-Bernstam3Carl Morrison4Joud Hajjar5Mingxuan Xu6Anas Alshawa7Bettzy Stephen8Ying Yuan9Jordi Rodon Ahnert10Abdulrazzak Zarifa11Shrutii Sarda12Timothy Looney13Sapna P Patel14Geoffrey M Lowman15Dzifa Yawa Duose16Jeffrey M Conroy17Evan Kwiatkowski181The University of Texas MD Anderson Cancer Center, Houston, TX, USA6The University of Texas MD Anderson Cancer Center, Houston, TX, USAInvestigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA1The University of Texas MD Anderson Cancer Center, Houston, TX, USARoswell Park Comprehensive Cancer Center, Buffalo, New York, USAAdult Allergy and Immunology, Baylor College of Medicine and Texas Children`s Hospital, Houston, Texas, USAInvestigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USAInvestigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA1The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA1The University of Texas MD Anderson Cancer Center, Houston, TX, USAThermo Fisher Scientific, Carlsbad, California, USAThermo Fisher Scientific, Clinical Next-Generation Sequencing, Austin, Texas, USA15University of Colorado, Houston, TX, USAThermo Fisher Scientific, Carlsbad, California, USATranslational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA2Labcorp Oncology, Durham, NC, USADepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USABackground Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past.Patients and methods We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3).Results Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs.Conclusion The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.https://jitc.bmj.com/content/11/8/e007236.full |
| spellingShingle | Linghua Wang Siqing Fu Aung Naing Funda Meric-Bernstam Carl Morrison Joud Hajjar Mingxuan Xu Anas Alshawa Bettzy Stephen Ying Yuan Jordi Rodon Ahnert Abdulrazzak Zarifa Shrutii Sarda Timothy Looney Sapna P Patel Geoffrey M Lowman Dzifa Yawa Duose Jeffrey M Conroy Evan Kwiatkowski T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy Journal for ImmunoTherapy of Cancer |
| title | T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy |
| title_full | T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy |
| title_fullStr | T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy |
| title_full_unstemmed | T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy |
| title_short | T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy |
| title_sort | t cell receptor beta variable gene polymorphism predicts immune related adverse events during checkpoint blockade immunotherapy |
| url | https://jitc.bmj.com/content/11/8/e007236.full |
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