Circulating T-cell receptor repertoire for cancer early detection
Abstract Liquid biopsy is a promising non-invasive technology that is capable of diagnosing cancer. However, current ctDNA-based approaches detect only a minority of early-stage disease. We set out to improve the sensitivity of liquid biopsy by harnessing tumor recognition by T cells through the seq...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01036-y |
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| author | Yilong Li Michelle Nahas Dennis Stephens Kate Froburg Emma Hintz Devin Champagne Amaneet Lochab Markus Brown Jasper Braun María Antonia Fortuño María-del-Mar Ocón Andrea Pasquier Inés Luque-Vázquez Hita Moudgalya Sophie Kivlehan Iliana Gjeci Stephanie L. Korle Arantza Campo Maria Rodriguez Christopher W. Seder Patrick H. Lizotte Raphael Bueno Jeffrey A. Borgia Luis M. Seijo Luis M. Montuenga Roman Yelensky |
| author_facet | Yilong Li Michelle Nahas Dennis Stephens Kate Froburg Emma Hintz Devin Champagne Amaneet Lochab Markus Brown Jasper Braun María Antonia Fortuño María-del-Mar Ocón Andrea Pasquier Inés Luque-Vázquez Hita Moudgalya Sophie Kivlehan Iliana Gjeci Stephanie L. Korle Arantza Campo Maria Rodriguez Christopher W. Seder Patrick H. Lizotte Raphael Bueno Jeffrey A. Borgia Luis M. Seijo Luis M. Montuenga Roman Yelensky |
| author_sort | Yilong Li |
| collection | DOAJ |
| description | Abstract Liquid biopsy is a promising non-invasive technology that is capable of diagnosing cancer. However, current ctDNA-based approaches detect only a minority of early-stage disease. We set out to improve the sensitivity of liquid biopsy by harnessing tumor recognition by T cells through the sequencing of the circulating T-cell receptor repertoire. We studied a cohort of 463 patients with lung cancer (86% stage I) and 587 subjects without cancer using gDNA extracted from blood buffy coats. We performed TCR β chain sequencing to yield a median of 113,571 TCR clonotypes per sample and built a TCR sequence similarity graph to cluster clonotypes into TCR repertoire functional units (RFUs). The TCR frequencies of RFUs were tested for association with cancer status and RFUs with a statistically significant association were combined into a cancer score using a support vector machine model. The model was evaluated by 10-fold cross-validation and compared with a ctDNA panel of 237 mutation hotspots in 154 lung cancer driver genes and 17 cancer related protein biomarkers in 85 subjects. We identified 327 cancer-associated TCR RFUs with a false discovery rate (FDR) ≤ 0.1, including 157 enriched in cancer samples and 170 enriched in controls. Levels of 247/327 (76%) RFUs were correlated with the presence of an HLA allele at FDR ≤ 0.1 and tumor-infiltrating lymphocyte TCRs from multiple RFUs bound HLA presented tumor antigen peptides, suggesting antigen recognition as a driver of the cancer-RFU associations found. The RFU cancer score detected nearly 50% of stage I lung cancers at a specificity of 80% and boosted the sensitivity by up to 20 percentage points when added to ctDNA and circulating proteins in a multi-analyte cancer screening test. Overall, we show that circulating TCR repertoire functional unit analysis can complement established analytes to improve liquid biopsy sensitivity for early-stage cancer. |
| format | Article |
| id | doaj-art-be8cd7d562ee4678a1b2a5a851bd42be |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-be8cd7d562ee4678a1b2a5a851bd42be2025-08-20T03:45:44ZengNature Portfolionpj Precision Oncology2397-768X2025-07-019111210.1038/s41698-025-01036-yCirculating T-cell receptor repertoire for cancer early detectionYilong Li0Michelle Nahas1Dennis Stephens2Kate Froburg3Emma Hintz4Devin Champagne5Amaneet Lochab6Markus Brown7Jasper Braun8María Antonia Fortuño9María-del-Mar Ocón10Andrea Pasquier11Inés Luque-Vázquez12Hita Moudgalya13Sophie Kivlehan14Iliana Gjeci15Stephanie L. Korle16Arantza Campo17Maria Rodriguez18Christopher W. Seder19Patrick H. Lizotte20Raphael Bueno21Jeffrey A. Borgia22Luis M. Seijo23Luis M. Montuenga24Roman Yelensky25Serum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncSerum Detect, IncClínica Universidad de Navarra Cancer CenterClínica Universidad de Navarra Cancer CenterClínica Universidad de Navarra Cancer CenterClínica Universidad de Navarra Cancer CenterRush University Medical Center Department of Anatomy & Cell BiologyDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDivision of Thoracic Surgery, Brigham and Women’s HospitalPulmonary Department, Clínica Universidad de NavarraThoracic Surgery Department, Clínica Universidad de NavarraRush University Medical Center Department of Cardiovascular and Thoracic SurgeryDepartment of Medical Oncology, Dana-Farber Cancer InstituteDivision of Thoracic Surgery, Brigham and Women’s HospitalRush University Medical Center Department of Anatomy & Cell BiologyClínica Universidad de Navarra Cancer CenterClínica Universidad de Navarra Cancer CenterSerum Detect, IncAbstract Liquid biopsy is a promising non-invasive technology that is capable of diagnosing cancer. However, current ctDNA-based approaches detect only a minority of early-stage disease. We set out to improve the sensitivity of liquid biopsy by harnessing tumor recognition by T cells through the sequencing of the circulating T-cell receptor repertoire. We studied a cohort of 463 patients with lung cancer (86% stage I) and 587 subjects without cancer using gDNA extracted from blood buffy coats. We performed TCR β chain sequencing to yield a median of 113,571 TCR clonotypes per sample and built a TCR sequence similarity graph to cluster clonotypes into TCR repertoire functional units (RFUs). The TCR frequencies of RFUs were tested for association with cancer status and RFUs with a statistically significant association were combined into a cancer score using a support vector machine model. The model was evaluated by 10-fold cross-validation and compared with a ctDNA panel of 237 mutation hotspots in 154 lung cancer driver genes and 17 cancer related protein biomarkers in 85 subjects. We identified 327 cancer-associated TCR RFUs with a false discovery rate (FDR) ≤ 0.1, including 157 enriched in cancer samples and 170 enriched in controls. Levels of 247/327 (76%) RFUs were correlated with the presence of an HLA allele at FDR ≤ 0.1 and tumor-infiltrating lymphocyte TCRs from multiple RFUs bound HLA presented tumor antigen peptides, suggesting antigen recognition as a driver of the cancer-RFU associations found. The RFU cancer score detected nearly 50% of stage I lung cancers at a specificity of 80% and boosted the sensitivity by up to 20 percentage points when added to ctDNA and circulating proteins in a multi-analyte cancer screening test. Overall, we show that circulating TCR repertoire functional unit analysis can complement established analytes to improve liquid biopsy sensitivity for early-stage cancer.https://doi.org/10.1038/s41698-025-01036-y |
| spellingShingle | Yilong Li Michelle Nahas Dennis Stephens Kate Froburg Emma Hintz Devin Champagne Amaneet Lochab Markus Brown Jasper Braun María Antonia Fortuño María-del-Mar Ocón Andrea Pasquier Inés Luque-Vázquez Hita Moudgalya Sophie Kivlehan Iliana Gjeci Stephanie L. Korle Arantza Campo Maria Rodriguez Christopher W. Seder Patrick H. Lizotte Raphael Bueno Jeffrey A. Borgia Luis M. Seijo Luis M. Montuenga Roman Yelensky Circulating T-cell receptor repertoire for cancer early detection npj Precision Oncology |
| title | Circulating T-cell receptor repertoire for cancer early detection |
| title_full | Circulating T-cell receptor repertoire for cancer early detection |
| title_fullStr | Circulating T-cell receptor repertoire for cancer early detection |
| title_full_unstemmed | Circulating T-cell receptor repertoire for cancer early detection |
| title_short | Circulating T-cell receptor repertoire for cancer early detection |
| title_sort | circulating t cell receptor repertoire for cancer early detection |
| url | https://doi.org/10.1038/s41698-025-01036-y |
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