Galectin-9 (Gal-9) has been known to bind glycans on Tim-3 and induce apoptotic cell death in T cells via cross-linked Tim-3/Gal-9/Tim-3. Yang and Sun et al. showed that Gal-9 also bound specifically to PD-1, forming competing cross-linked PD-1/Gal-9/Tim3 lattices in PD-1+TIM-3+ cells that resisted Gal-9-induced cell death. In tumor models, anti-Gal-9 monotherapy modestly expanded cytotoxic Tim3+CD8+ T cells and Tregs. Combining anti-Gal-9 with agonist anti-GITR greatly depleted Tregs, suppressed tumor growth, and prolonged survival. Interferons (β and γ) upregulated Gal-9 expression and secretion, suggesting Gal-9 could be a targetable, adaptive resistance mechanism.
Contributed by Katherine Turner
ABSTRACT: 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 (Treg 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 Treg 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.