The Library
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
Tools
Tools
Tools
Marcinek, Anetta, Brauchle, Bettina, Rohrbacher, Lisa, Hänel, Gerulf, Philipp, Nora, Märkl, Florian, Strzalkowski, Thaddäus, Lacher, Sonja M., Udiljak, Dragica, Spiekermann, Karsten, Theurich, Sebastian, Kobold, Sebastian, Kischel, Roman, James, John R., Bücklein, Veit L. and Subklewe, Marion (2023) 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. Cancer Immunology, Immunotherapy, 72 . pp. 2499-2512. doi:10.1007/s00262-023-03439-x ISSN 0340-7004.
|
PDF
WRAP-CD33-BiTE-molecule-mediated-immune-synapse-formation-subsequent-T-cell-activation-determined-expression-profile-activating-inhibitory-checkpoint-molecules-AML-cells-James-2023.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (1408Kb) | Preview |
Official URL: https://doi.org/10.1007/s00262-023-03439-x
Abstract
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.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subjects: | Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Immune response -- Molecular aspects, Biological response modifiers, T cells, T cells -- Receptors, Acute myeloid leukemia -- Treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Cancer Immunology, Immunotherapy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | Springer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 0340-7004 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Official Date: | July 2023 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dates: |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 72 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Page Range: | pp. 2499-2512 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1007/s00262-023-03439-x | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 27 April 2023 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 28 April 2023 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
|
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
Downloads
Downloads per month over past year
