![]() However, persistent antigen stimulation in chronic viral infection and cancer leads to T cell exhaustion, a state of T cell dysfunction regulated primarily by the master regulators TOX 3 and TCF-1 4, 5, and developed after precursor exhausted T cells (TCF1 +PD-1 intTIM-3 –) differentiate into terminally exhausted T cells (TCF1 –PD-1 hiTIM-3 +) 6, 7, 8, 9, 10. Under normal physiological conditions, immune response is kept in check by immune checkpoints to prevent autoimmunity. ![]() The frequency and activity of these cells are regulated by a balance of co-stimulatory and co-inhibitory signals that are collectively termed immune checkpoints 2. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.ĬD8 T cells kill tumor cells directly during antitumor immune response, and tumor infiltration of CD8 T cells positively correlates with patient prognosis in a wide range of malignancies 1. 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. 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. Anti-Gal-9 therapy selectively expands intratumoral TIM-3 + cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T reg cells). 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. 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.
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