Prognostic impact of enhanced CD96 expression on NK cells by TGF-β1 in AML

• Published in: International immunopharmacology 2024-11, Vol.141, p.112958, Article 112958
• Main Authors: Zhang, Qi, Huang, Ting, Li, Xiaomin, Liu, Guanfang, Xian, Luhua, Mao, Xueying, Lin, Ting, Fu, Cheng, Chen, Xiangming, Liang, Wenting, Zheng, Yanling, Zhao, Yuyang, Lin, Qiwen, Xu, Xiuzhang, Lin, Yu, Bu, Jin, Wu, Changyou, Zhou, Maohua, Shen, Erxia
• Format: Article
• Language: English
• Subjects: Adult; Aged; AML; Antigens, CD - metabolism; CD96; Cell Line, Tumor; Cytotoxicity, Immunologic; Female; Humans; Interferon-gamma - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - immunology; Male; Middle Aged; Prognosis; Signal Transduction; Smad3 Protein - metabolism; TGF-β; Transforming Growth Factor beta1 - metabolism; Young Adult
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112958

•Increased CD96 expression on NK cells: AML patients show enhanced CD96 expression on NK cells at initial diagnosis, indicating a dysfunctional NK cell phenotype.•CD96 blockade enhances NK cell cytotoxicity: Blocking CD96 significantly improves NK cell cytotoxicity against leukemia cells, suggesting therapeutic potential.•CD96+ NK cells as a prognostic marker: A high frequency of CD96+ NK cells is associated with poor clinical outcomes in AML patients, highlighting its prognostic significance.•Role of TGF-β1 in CD96 up-regulation: TGF-β1 up-regulates CD96 expression on NK cells via SMAD3 signaling, identifying a pathway that may be targeted for therapeutic intervention. Acute myeloid leukemia (AML) is one of the most common types of blood cancer in adults and is associated with a poor survival rate. NK cells play a crucial role in combating AML, and alterations in immune checkpoint expression can impair NK cell function against AML. Targeting certain checkpoints may restore this function. CD96, an inhibitory immune checkpoint, has unclear expression and roles on NK cells in AML patients. In this study, we initially evaluated CD96 expression and compared CD96+ NK with the inhibitory receptor and stimulatory receptors on NK cells from AML patients at initial diagnosis. We observed increased CD96 expression on NK cells with dysfunctional phenotype. Further analysis revealed that CD96+ NK cells had lower IFN-γ production than CD96- NK cells. Blocking CD96 enhanced the cytotoxicity of primary NK and cord blood-derived NK (CB-NK) cells against leukemia cells. Notably, patients with a high frequency of CD96+ NK cells at initial diagnosis exhibited poorer clinical outcomes. Additionally, TGF-β1 was found to enhance CD96 expression on NK cells via SMAD3 signaling. These findings suggest that CD96 is invovled in NK dysfunction against AML blast, and might be a potential target for restoring NK cell function in the fight against AML.