Cargando…

Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to th...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Riyao, Sun, Linlin, Li, Ching-Fei, Wang, Yu-Han, Yao, Jun, Li, Hui, Yan, Meisi, Chang, Wei-Chao, Hsu, Jung-Mao, Cha, Jong-Ho, Hsu, Jennifer L., Chou, Cheng-Wei, Sun, Xian, Deng, Yalan, Chou, Chao-Kai, Yu, Dihua, Hung, Mien-Chie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864927/
https://www.ncbi.nlm.nih.gov/pubmed/33547304
http://dx.doi.org/10.1038/s41467-021-21099-2
Descripción
Sumario:The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1(+)TIM-3(+) T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3(+) cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T(reg) cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T(reg) cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.