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

  • Nat Commun. 2021 Feb 5;12(1):832. doi: 10.1038/s41467-021-21099-2.
Riyao Yang  #  1 ,  Linlin Sun  #  2  3 ,  Ching-Fei Li  2 ,  Yu-Han Wang  2  4 ,  Jun Yao  2 ,  Hui Li  2  5 ,  Meisi Yan  2  6 ,  Wei-Chao Chang  4 ,  Jung-Mao Hsu  2  4 ,  Jong-Ho Cha  2  7 ,  Jennifer L Hsu  2 ,  Cheng-Wei Chou  2  4  8 ,  Xian Sun  2  9 ,  Yalan Deng  2 ,  Chao-Kai Chou  2 ,  Dihua Yu  2 ,  Mien-Chie Hung  10  11
Affiliations
  • 1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
  • 4. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 5. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China.
  • 6. Department of Pathology, Harbin Medical University, Harbin, China.
  • 7. Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea.
  • 8. Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
  • 9. Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 10. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 11. Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. [email protected].
  • # Contributed equally.
PMID: 33547304 DOI: 10.1038/s41467-021-21099-2
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.

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