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Medientyp:
E-Artikel
Titel:
DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity
Beteiligte:
Kureshi, Rakeeb;
Bello, Elisa;
Kureshi, Courtney T.S.;
Walsh, Michael J.;
Lippert, Victoria;
Hoffman, Megan T.;
Dougan, Michael;
Longmire, Tyler;
Wichroski, Michael;
Dougan, Stephanie K.
Erschienen:
American Association for the Advancement of Science (AAAS), 2023
Erschienen in:
Science Advances, 9 (2023) 47
Sprache:
Englisch
DOI:
10.1126/sciadv.adk1853
ISSN:
2375-2548
Entstehung:
Anmerkungen:
Beschreibung:
Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1 high and TRP1 low ), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1 high and TRP1 low CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1 high - and TRP1 low -mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-γ, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.