Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy
説明
<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup>TIM-3<jats:sup>+</jats:sup> 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<jats:sup>+</jats:sup> cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T<jats:sub>reg</jats:sub> 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<jats:sub>reg</jats:sub> 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.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 12 (1), 832-, 2021-02-05
Springer Science and Business Media LLC