Disulfiram bolsters T-cell anti-tumor immunity through direct activation of LCK-mediated TCR signaling.
EMBO J
; 41(16): e110636, 2022 08 16.
Article
en En
| MEDLINE
| ID: mdl-35638332
ABSTRACT
Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin-2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti-tumor immunity against both melanoma and colon cancer in mice by activating CD8+ T cells, and this effect was enhanced by anti-PD-1 co-treatment. We conclude that DSF directly activates LCK-mediated TCR signaling to induce strong anti-tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito
/
Disulfiram
Límite:
Animals
Idioma:
En
Revista:
EMBO J
Año:
2022
Tipo del documento:
Article
País de afiliación:
China