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Background <p>The roles of NKG2A–HLA-E and TIM3–galectin 9 immune checkpoint pathways in pancreatic ductal adenocarcinoma (PDAC) progression remain incompletely characterized. This study investigates their contributions to PDAC and therapeutic potential.</p> Methods <p>The expressions of ligands HLA-E and galectin 9 and receptors NKG2A and TIM3 were analyzed through bioinformatics, immunohistochemistry, and flow cytometry. Effects of HLA-E and galectin 9 overexpression on pancreatic epithelial cells were assessed by Transwell, wound healing, and CCK-8 assays. Ligand–receptor interactions and their impact on lymphocyte function were examined by multiplex immunofluorescence, single-cell RNA-sequencing, and functional assays.</p> Results <p>The expression of ligands HLA-E and galectin 9 was elevated in PDAC cancer tissues compared with both normal tissues and benign lesions. The overexpression of HLA-E enhanced the migratory and invasive ability of pancreatic epithelial cells. Moreover, the high expression of HLA-E and galectin 9 correlated with worse overall survival in PDAC patients. Mechanistically, increased NKG2A expression in both tumor stroma and parenchyma was associated with impaired function of tumor-infiltrating T cells and NK cells.&#xa0;Spatial analyses further revealed colocalization of NKG2A⁺ T cells with high HLA-E-expressing tumor regions, indicating an active and localized immunosuppressive circuit. Single-cell profiling showed that NKG2A⁺ and TIM3⁺ tumor-infiltrating T cells exhibited exhausted signatures, particularly when co-expressing PD-1. Importantly, dual blockade of NKG2A or TIM3 with PD-1 enhanced the anti-tumor response of CD8⁺ and CD4⁺ T cells, mediated by SHP-1 inhibition and ERK activation.</p> Conclusions <p>This study identifies NKG2A–HLA-E and TIM3–galectin 9 pathways as key mechanisms in PDAC progression and immune inhibition and provides a mechanistic rationale for combining their blockade with PD-1-PD-L1 blockade as a potential therapeutic strategy.</p>

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NKG2A–HLA-E and TIM3–galectin 9 pathways promote immune inhibition and represent therapeutic vulnerabilities in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Yuanyu Lin,
  • Wanhua Feng,
  • Yan Li,
  • Yisen Tang,
  • Xiaomei Zhuang,
  • Yingzi Huang,
  • Juping Xie,
  • Kai Liu,
  • Youwen Fan,
  • Yajun Tang,
  • Dong Li,
  • Ziming He,
  • Yuxiong Qiu,
  • Junzong Chen,
  • Jie Xu,
  • Zheng Yang,
  • Linxiang Lan,
  • Di Tang,
  • Gang Deng,
  • Guoying Zhou

摘要

Background

The roles of NKG2A–HLA-E and TIM3–galectin 9 immune checkpoint pathways in pancreatic ductal adenocarcinoma (PDAC) progression remain incompletely characterized. This study investigates their contributions to PDAC and therapeutic potential.

Methods

The expressions of ligands HLA-E and galectin 9 and receptors NKG2A and TIM3 were analyzed through bioinformatics, immunohistochemistry, and flow cytometry. Effects of HLA-E and galectin 9 overexpression on pancreatic epithelial cells were assessed by Transwell, wound healing, and CCK-8 assays. Ligand–receptor interactions and their impact on lymphocyte function were examined by multiplex immunofluorescence, single-cell RNA-sequencing, and functional assays.

Results

The expression of ligands HLA-E and galectin 9 was elevated in PDAC cancer tissues compared with both normal tissues and benign lesions. The overexpression of HLA-E enhanced the migratory and invasive ability of pancreatic epithelial cells. Moreover, the high expression of HLA-E and galectin 9 correlated with worse overall survival in PDAC patients. Mechanistically, increased NKG2A expression in both tumor stroma and parenchyma was associated with impaired function of tumor-infiltrating T cells and NK cells. Spatial analyses further revealed colocalization of NKG2A⁺ T cells with high HLA-E-expressing tumor regions, indicating an active and localized immunosuppressive circuit. Single-cell profiling showed that NKG2A⁺ and TIM3⁺ tumor-infiltrating T cells exhibited exhausted signatures, particularly when co-expressing PD-1. Importantly, dual blockade of NKG2A or TIM3 with PD-1 enhanced the anti-tumor response of CD8⁺ and CD4⁺ T cells, mediated by SHP-1 inhibition and ERK activation.

Conclusions

This study identifies NKG2A–HLA-E and TIM3–galectin 9 pathways as key mechanisms in PDAC progression and immune inhibition and provides a mechanistic rationale for combining their blockade with PD-1-PD-L1 blockade as a potential therapeutic strategy.