Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors
| Autor: | Muliaditan, Tamara, Halim, Leena, Whilding, Lynsey M, Draper, Benjamin, Achkova, Daniela Y, Kausar, Fahima, Glover, Maya, Bechman, Natasha, Arulappu, Appitha, Sanchez, Jenifer, Flaherty, Katie R, Obajdin, Jana, Grigoriadis, Kristiana, Antoine, Pierre, Larcombe-Young, Daniel, Hull, Caroline M, Buus, Richard, Gordon, Peter, Grigoriadis, Anita, Davies, David M, Schurich, Anna, Maher, John, Afd Pharmacology, Pharmacology |
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| Přispěvatelé: | Afd Pharmacology, Pharmacology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Integrins
Lymphoma T-Lymphocytes Mice SCID CAR T cells General Biochemistry Genetics and Molecular Biology Article Tumor Necrosis Factor Receptor Superfamily Member 9 CD28 Antigens Antigens Neoplasm Mice Inbred NOD Cell Line Tumor Receptors Colony-Stimulating Factor Animals Humans cancer Receptors Chimeric Antigen chimeric antigen receptor Cell Membrane Mucin-1 co-stimulation parallel CAR Xenograft Model Antitumor Assays immunotherapy Protein Multimerization chimeric co-stimulatory receptor Signal Transduction |
| Zdroj: | Cell reports. Medicine, 2(12), 1. Cell Press Cell Reports Medicine |
| ISSN: | 2666-3791 |
| Popis: | Summary Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs. Graphical abstract Highlights • Juxta-membrane localization is required for effective CAR-mediated co-stimulation • To provide dual CD28 and 41BB co-stimulation, two fusion receptors are required • The resulting parallel CAR configuration promotes functional persistence of T cells • As a result, parallel CAR T cells mediate enhanced anti-tumor activity Dual co-stimulation by CD28 and 41BB contributes importantly to physiological immune responses, highlighting the desirability of harnessing these pathways to potentiate CAR T cell immunotherapy. Here, Muliaditan et al. show that this is achieved using a parallel CAR format, ensuring that both co-stimulatory domains sit in their natural membrane proximal location. |
| Databáze: | OpenAIRE |
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