Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests
Background Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/5/e006264.full |
| _version_ | 1797814585598672896 |
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| author | Steven A Rosenberg Paul Robbins Biman Paria Jared J Gartner Sri Krishna Satyajit Ray Rami Yossef Victoria Hill Frank J Lowery Praveen D Chatani Neilesh B Parikh Kyle J Hitscherich Maria Florentin Alakesh Bera Maria Parkhust |
| author_facet | Steven A Rosenberg Paul Robbins Biman Paria Jared J Gartner Sri Krishna Satyajit Ray Rami Yossef Victoria Hill Frank J Lowery Praveen D Chatani Neilesh B Parikh Kyle J Hitscherich Maria Florentin Alakesh Bera Maria Parkhust |
| author_sort | Steven A Rosenberg |
| collection | DOAJ |
| description | Background Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority.Methods We analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8+ TILTP).Results TILTP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TILTP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TILTP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TILTP clonotypes from four patients indicated that most in vitro expanded TILTP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition.Conclusions While direct usage of in vitro-expanded CD8+ TILTP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TILTP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer. |
| first_indexed | 2024-03-13T08:09:50Z |
| format | Article |
| id | doaj.art-cbbdaffbcb90479ea2c903c47528272b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-13T08:09:50Z |
| publishDate | 2023-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-cbbdaffbcb90479ea2c903c47528272b2023-05-31T23:30:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-05-0111510.1136/jitc-2022-006264Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digestsSteven A Rosenberg0Paul Robbins1Biman Paria2Jared J Gartner3Sri Krishna4Satyajit Ray5Rami Yossef6Victoria Hill7Frank J Lowery8Praveen D Chatani9Neilesh B Parikh10Kyle J Hitscherich11Maria Florentin12Alakesh Bera13Maria Parkhust14Surgery Branch, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, National Cancer Institute, Bethesda, Maryland, USAProgram Coordination and Referral Branch, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USADepartment of paediatrics, Royal Hospital for Children, Glasgow, UKSurgery Branch, National Cancer Institute, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USASurgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USABackground Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority.Methods We analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8+ TILTP).Results TILTP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TILTP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TILTP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TILTP clonotypes from four patients indicated that most in vitro expanded TILTP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition.Conclusions While direct usage of in vitro-expanded CD8+ TILTP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TILTP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer.https://jitc.bmj.com/content/11/5/e006264.full |
| spellingShingle | Steven A Rosenberg Paul Robbins Biman Paria Jared J Gartner Sri Krishna Satyajit Ray Rami Yossef Victoria Hill Frank J Lowery Praveen D Chatani Neilesh B Parikh Kyle J Hitscherich Maria Florentin Alakesh Bera Maria Parkhust Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests Journal for ImmunoTherapy of Cancer |
| title | Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests |
| title_full | Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests |
| title_fullStr | Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests |
| title_full_unstemmed | Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests |
| title_short | Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests |
| title_sort | cell surface marker based capture of neoantigen reactive cd8 t cell receptors from metastatic tumor digests |
| url | https://jitc.bmj.com/content/11/5/e006264.full |
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