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

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

Affiliations

  • 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ryang@mdanderson.org.
  • 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. mhung@cmu.edu.tw.
  • 11 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
  • # 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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