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

Riyao Yang (), Linlin Sun, Ching-Fei Li, Yu-Han Wang, Jun Yao, Hui Li, Meisi Yan, Wei-Chao Chang, Jung-Mao Hsu, Jong-Ho Cha, Jennifer L. Hsu, Cheng-Wei Chou, Xian Sun, Yalan Deng, Chao-Kai Chou, Dihua Yu and Mien-Chie Hung ()
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Riyao Yang: The University of Texas MD Anderson Cancer Center
Linlin Sun: The University of Texas MD Anderson Cancer Center
Ching-Fei Li: The University of Texas MD Anderson Cancer Center
Yu-Han Wang: The University of Texas MD Anderson Cancer Center
Jun Yao: The University of Texas MD Anderson Cancer Center
Hui Li: The University of Texas MD Anderson Cancer Center
Meisi Yan: The University of Texas MD Anderson Cancer Center
Wei-Chao Chang: China Medical University
Jung-Mao Hsu: The University of Texas MD Anderson Cancer Center
Jong-Ho Cha: The University of Texas MD Anderson Cancer Center
Jennifer L. Hsu: The University of Texas MD Anderson Cancer Center
Cheng-Wei Chou: The University of Texas MD Anderson Cancer Center
Xian Sun: The University of Texas MD Anderson Cancer Center
Yalan Deng: The University of Texas MD Anderson Cancer Center
Chao-Kai Chou: The University of Texas MD Anderson Cancer Center
Dihua Yu: The University of Texas MD Anderson Cancer Center
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21099-2

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