CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells
© 2023. The Author(s)..
Bispecific T-cell engager (BiTE®) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy.
| Errataetall: |
ErratumIn: Cancer Immunol Immunother. 2023 May 8;:. - PMID 37154851 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:72 |
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| Enthalten in: |
Cancer immunology, immunotherapy : CII - 72(2023), 7 vom: 11. Juli, Seite 2499-2512 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marcinek, Anetta [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.06.2023 Date Revised 16.06.2023 published: Print-Electronic ErratumIn: Cancer Immunol Immunother. 2023 May 8;:. - PMID 37154851 Citation Status MEDLINE |
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| doi: |
10.1007/s00262-023-03439-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35545680X |
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| 100 | 1 | |a Marcinek, Anetta |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 15.06.2023 | ||
| 500 | |a Date Revised 16.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Cancer Immunol Immunother. 2023 May 8;:. - PMID 37154851 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a Bispecific T-cell engager (BiTE®) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute myeloid leukemia | |
| 650 | 4 | |a Bispecific antibodies | |
| 650 | 4 | |a Checkpoint molecule (PD-L1) | |
| 650 | 4 | |a Costimulation (CD86) | |
| 650 | 4 | |a Immune synapse | |
| 650 | 7 | |a Antibodies, Bispecific |2 NLM | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a CD33 protein, human |2 NLM | |
| 650 | 7 | |a Immune Checkpoint Proteins |2 NLM | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 650 | 7 | |a Sialic Acid Binding Ig-like Lectin 3 |2 NLM | |
| 700 | 1 | |a Brauchle, Bettina |e verfasserin |4 aut | |
| 700 | 1 | |a Rohrbacher, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Hänel, Gerulf |e verfasserin |4 aut | |
| 700 | 1 | |a Philipp, Nora |e verfasserin |4 aut | |
| 700 | 1 | |a Märkl, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Strzalkowski, Thaddäus |e verfasserin |4 aut | |
| 700 | 1 | |a Lacher, Sonja M |e verfasserin |4 aut | |
| 700 | 1 | |a Udiljak, Dragica |e verfasserin |4 aut | |
| 700 | 1 | |a Spiekermann, Karsten |e verfasserin |4 aut | |
| 700 | 1 | |a Theurich, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Kobold, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Kischel, Roman |e verfasserin |4 aut | |
| 700 | 1 | |a James, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Bücklein, Veit L |e verfasserin |4 aut | |
| 700 | 1 | |a Subklewe, Marion |e verfasserin |4 aut | |
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