Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression  

作　　者：Zhihong Luo Xiaohua Huang Xinyi Xu Kefeng Wei Yi Zheng Ke Gong Wenhua Li 

机构地区：[1]Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,Wuhan University,Wuhan 430072,China [2]Wuhan University Shenzhen Research Institute,Shenzhen 518057,China [3]Central Laboratory,University of Chinese Academy of Sciences-Shenzhen Hospital,Shenzhen 518107,China [4]Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology,School of Basic Medical Sciences,Wuhan University,Wuhan 430071,China

出　　处：《Cancer Biology & Medicine》2024年第6期513-540,共28页癌症生物学与医学（英文版）

基　　金：supported by the Shenzhen Science and Technology Program (Grant no. JCYJ20230807090459001);the Joint Research Fund of the National Science Fund of China Science and Technology Development Fund of Macao SAR (No. 32161160303 for NSFC and No. 0010/2021/AFJ for FDCT);the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (Grant no. ZNJC202330)。

摘　　要：Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a the

关 键 词：Breast cancer lactate dehydrogenase B lactic acid NK cells tumor immunity 

分 类 号：R737.9[医药卫生—肿瘤]