Single-cell transcriptome analysis of CAR T-cell products reveals subpopulations, stimulation, and exhaustion signatures
| Autor: | Berthold Göttgens, Fernando J Calero-Nieto, Carlotta Peticone, Xiaonan Wang, Ekaterini Kotsopoulou |
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| Přispěvatelé: | Wang, Xiaonan [0000-0003-3759-778X], Peticone, Carlotta [0000-0001-5665-6859], Göttgens, Berthold [0000-0001-6302-5705], Calero-Nieto, Fernando J [0000-0003-3358-8253], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Immunology Stimulation Biology Peripheral blood mononuclear cell Immunotherapy Adoptive CAR-T exhaustion Flow cytometry Transcriptome 03 medical and health sciences 0302 clinical medicine Antigen medicine Immunology and Allergy Gene RC254-282 Original Research medicine.diagnostic_test chimeric antigen receptor T cell activation Gene Expression Profiling Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC581-607 Chimeric antigen receptor 3. Good health Cell biology 030104 developmental biology Oncology 030220 oncology & carcinogenesis Leukocytes Mononuclear Car t cells Immunologic diseases. Allergy single-cell transcriptomics human activities Research Article |
| Zdroj: | OncoImmunology, Vol 10, Iss 1 (2021) Oncoimmunology article-version (VoR) Version of Record |
| Popis: | Chimeric antigen receptor (CAR) T-cell adoptive therapy is set to transform the treatment of a rapidly expanding range of malignancies. Although the activation process of normal T cells is well characterized, comparatively little is known about the activation of cells via the CAR. Here we have used flow cytometry together with single-cell transcriptome profiling to characterize the starting material (peripheral blood mononuclear cells) and CAR therapeutic products of 3 healthy donors in the presence and absence of antigen-specific stimulation. Analysis of 53,191 single-cell transcriptomes showed APRIL-based CAR products to contain several subpopulations of cells, with cellular composition reproducible from donor to donor, and all major cellular subsets compatible with CAR expression. Only 50% of CAR-expressing cells displayed transcriptional changes upon CAR-specific antigen exposure. The resulting molecular signature for CAR T-cell activation provides a rich resource for future dissection of underlying mechanisms. Targeted data interrogation also revealed that a small proportion of antigen-responding CAR-expressing cells displayed an exhaustion signature, with both known markers and genes not previously associated with T-cell exhaustion. Comprehensive single-cell transcriptomic analysis thus represents a powerful way to guide the assessment and optimization of clinical-grade CAR-T-cells, and inform future research into the underlying molecular processes. |
| Databáze: | OpenAIRE |
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