Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies
T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/2/e003655.full |
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| author | Melanie Märklin Gundram Jung Jonas S Heitmann Helmut R Salih Martina Svenja Lutz Boris Klimovich Stefanie Maurer Latifa Zekri Clemens Hinterleitner |
| author_facet | Melanie Märklin Gundram Jung Jonas S Heitmann Helmut R Salih Martina Svenja Lutz Boris Klimovich Stefanie Maurer Latifa Zekri Clemens Hinterleitner |
| author_sort | Melanie Märklin |
| collection | DOAJ |
| description | T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4+ and CD8+ T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-β)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-β axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment. |
| format | Article |
| id | doaj-art-963a9f7859974fbaae2d3a15ce5ef74b |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-963a9f7859974fbaae2d3a15ce5ef74b2025-08-20T02:49:54ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-02-0110210.1136/jitc-2021-003655Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodiesMelanie Märklin0Gundram Jung1Jonas S Heitmann2Helmut R Salih3Martina Svenja Lutz4Boris Klimovich5Stefanie Maurer6Latifa Zekri7Clemens Hinterleitner8Cluster of Excellence iFIT (EXC 2180) Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany3Department for Immunology and German Cancer Consortium (DKTK), University of Tübingen, Tübingen, Baden-Württemberg, Germany2Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tuebingen, Tuebingen, Baden-Wuerttemberg, GermanyCCU Translational Immunology, Department of Internal Medicine, UKT, Tubingen, GermanyCCU Translational Immunology, Department of Internal Medicine, UKT, Tubingen, GermanyClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, GermanyImmunBridge, San Francisco, CA, USA1 Department of Immunology, University of Tübingen Interfaculty Institute of Cell Biology, Tubingen, GermanyCluster of Excellence iFIT (EXC 2180) Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tubingen, GermanyT cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4+ and CD8+ T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-β)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-β axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment.https://jitc.bmj.com/content/10/2/e003655.full |
| spellingShingle | Melanie Märklin Gundram Jung Jonas S Heitmann Helmut R Salih Martina Svenja Lutz Boris Klimovich Stefanie Maurer Latifa Zekri Clemens Hinterleitner Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies Journal for ImmunoTherapy of Cancer |
| title | Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies |
| title_full | Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies |
| title_fullStr | Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies |
| title_full_unstemmed | Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies |
| title_short | Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies |
| title_sort | platelets subvert antitumor efficacy of t cell recruiting bispecific antibodies |
| url | https://jitc.bmj.com/content/10/2/e003655.full |
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