Cancer immunology, immunotherapy : CII · 2026
NKG2A-HLA-E and TIM3-galectin 9 pathways promote immune inhibition and represent therapeutic vulnerabilities in pancreatic ductal adenocarcinoma.
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Lin Yuanyu, Feng Wanhua, Li Yan, Tang Yisen, Zhuang Xiaomei, Huang Yingzi, Xie Juping, Liu Kai, Fan Youwen, Tang Yajun, Li Dong, He Ziming, Qiu Yuxiong, Chen Junzong, Xu Jie, Yang Zheng, Lan Linxiang, Tang Di, Deng Gang, Zhou Guoying
Аннотация
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.
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.