CD39hi identifies an exhausted tumor-reactive CD8+ T cell population associated with tumor progression in human gastric cancer

作者：Yang Shen, Yuan Qiu, Zhen‐quan Duan, Yu-Xian Li, Ying Wang, Yuanyuan Zhang, Bao‐hang Zhu, YU Xiao-hong, Xue‐ling Tan, Weisan Chen, Yuan Zhuang, Quanming Zou, Daiyuan Ma, Liu‐sheng Peng · 发表于：Pharmacological Research · 年份：2024 · DOI：10.1016/j.phrs.2024.107122 · 被引用次数：17 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction、Adenosine and Purinergic Signaling

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with feature of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients’ poor overall survival. These finding provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may ...