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  3. Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation

Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation

  • Cell Mol Immunol. 2025 Mar;22(3):260-281. doi: 10.1038/s41423-024-01253-8.
Ngar-Woon Kam 1 2,  Cho Yiu Lau 1 2,  Jeffrey Yan Ho Lau 3,  Xin Dai 2 4,  Yusi Liang 3,  Syrus Pak Hei Lai 3,  Michael King Yung Chung 3,  Valen Zhuoyou Yu 1,  Wenting Qiu 5,  Mengsu Yang 5,  Corey Smith 6,  Rajiv Khanna 6,  Kwan Ming Ng 2,  Wei Dai 1,  Chi Ming Che 2 7,  Victor Ho-Fun Lee 8 9,  Dora L W Kwong 10 11
Affiliations

Affiliations

  • 1 Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2 Laboratory of Synthetic Chemistry and Chemical Biology Limited, Hong Kong, China.
  • 3 LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 4 Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 5 Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong, China.
  • 6 QIMR Centre for Immunotherapy and Vaccine Development and Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
  • 7 Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong, China.
  • 8 Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. vhflee@hku.hk.
  • 9 Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. vhflee@hku.hk.
  • 10 Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. dlwkwong@hku.hk.
  • 11 Clinical Oncology Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. dlwkwong@hku.hk.
PMID: 39910335 DOI: 10.1038/s41423-024-01253-8
Abstract

Immune effector cells, including cytotoxic T lymphocytes (CTLs) play essential roles in eliminating Cancer cells. However, their functionality is often compromised, even when they infiltrate the tumor microenvironment (TME) or are transferred to Cancer patients adoptively. In this study, we focused on Galectin 9 (G9), an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8 + CTL in the TME of nasopharyngeal carcinoma (NPC). We discovered that cell-cell contact between activated effector CTLs and target tumor cells (TarTC) with G9 overexpression led to cellular death defects. Despite the formation of CTL-TarTC conjugates, there is no impact on the cell number nor viability of CTL, and the release of cytolytic content and associated activity were not completely abrogated. Instead, this interaction promoted Autophagy and restricted necrosis in the TarTC. Furthermore, reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL. Additionally, inhibiting Autophagy effectively controlled tumor growth in cases of G9 overexpression. Therefore, we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells, characterized by increased Autophagy and decreased necrosis.

Keywords

Cell death; Cytotoxic T cells; Galectin 9; Immunotherapy; Nasopharyngeal carcinoma; Tumor microenvironment.

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