Augmenting TCR signal strength and ICOS costimulation results in metabolically fit and therapeutically potent human CAR Th17 cells

IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4+ T cells, the degree to which T cell antigen receptor (TCR) and cost...

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Veröffentlicht in:Molecular therapy 2023-07, Vol.31 (7), p.2120-2131
Hauptverfasser: Wyatt, Megan M., Huff, Logan W., Nelson, Michelle H., Neal, Lillian R., Medvec, Andrew R., Rangel Rivera, Guillermo O., Smith, Aubrey S., Rivera Reyes, Amalia M., Knochelmann, Hannah M., Riley, James L., Lesinski, Gregory B., Paulos, Chrystal M.
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Sprache:eng
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Zusammenfassung:IL-17-producing antigen-specific human T cells elicit potent antitumor activity in mice. Yet, refinement of this approach is needed to position it for clinical use. While activation signal strength regulates IL-17 production by CD4+ T cells, the degree to which T cell antigen receptor (TCR) and costimulation signal strength influences Th17 immunity remains unknown. We discovered that decreasing TCR/costimulation signal strength by incremental reduction of αCD3/costimulation beads progressively altered Th17 phenotype. Moreover, Th17 cells stimulated with αCD3/inducible costimulator (ICOS) beads produced more IL-17A, IFNγ, IL-2, and IL-22 than those stimulated with αCD3/CD28 beads. Compared with Th17 cells stimulated with the standard, strong signal strength (three beads per T cell), Th17 cells propagated with 30-fold fewer αCD3/ICOS beads were less reliant on glucose and favored the central carbon pathway for bioenergetics, marked by abundant intracellular phosphoenolpyruvate (PEP). Importantly, Th17 cells stimulated with weak αCD3/ICOS beads and redirected with a chimeric antigen receptor that recognizes mesothelin were more effective at clearing human mesothelioma. Less effective CAR Th17 cells generated with high αCD3/ICOS beads were rescued by overexpressing phosphoenolpyruvate carboxykinase 1 (PCK1), a PEP regulator. Thus, Th17 therapy can be improved by using fewer activation beads during manufacturing, a finding that is cost effective and directly translatable to patients. [Display omitted] Wyatt and colleagues discovered that human Th17 CAR-T cells generated with lower TCR activation strength and ICOS costimulation have improved function and metabolic fitness and can regress solid tumors to a greater extent than cells generated with higher activation signal strength, resulting in a cost-saving approach to CAR-T cell manufacturing.
ISSN:1525-0016
1525-0024
1525-0024
DOI:10.1016/j.ymthe.2023.04.010