Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis
Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis
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DOI：
10.1158/2326-6066.cir-18-0481
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发表时间：
2019-02-01
影响因子：
10.1
通讯作者：
O'Farrelly, Cliona
中科院分区：
文献类型：
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作者：
Harmon, Cathal;Robinson, Mark W.;O'Farrelly, Cliona
结直肠癌是全球第三大常见恶性肿瘤，每年新增病例达130万例。肝转移是这些患者死亡的主要原因。在人体肝脏中，转移性癌细胞必须逃避具有强大细胞毒性能力的肝脏驻留自然杀伤（NK）细胞群。在此，我们研究了这些肿瘤如何逃避肝脏NK细胞的监视。从接受结直肠肝转移（CRLM，n = 18）切除手术的患者获取组织活检样本，分别取自肿瘤、邻近组织和远端切除边缘。通过流式细胞术分析每个部位肝脏驻留NK细胞的数量和表型。制备肿瘤条件培养基（TCM）用于细胞因子和代谢物定量，并用于处理从移植过程中供体肝脏灌注液中分离出的健康肝脏驻留NK细胞。CRLM肿瘤中肝脏驻留NK细胞显著减少。暴露于TCM的健康肝脏驻留NK细胞在体外发生凋亡，且与乳酸升高有关。肿瘤浸润的肝脏驻留NK细胞显示出线粒体应激的迹象，通过用乳酸处理肝脏驻留NK细胞在体外重现了这一现象。乳酸通过降低NK细胞的细胞内pH诱导凋亡，导致线粒体功能障碍，而阻断线粒体活性氧（ROS）积累可防止这种情况发生。CRLM肿瘤产生乳酸，从而降低了肿瘤微环境的pH。向肿瘤迁移的肝脏驻留NK细胞无法调节细胞内pH，导致线粒体应激和凋亡。针对CRLM代谢为恢复局部NK细胞活性和防止肿瘤生长提供了一种有前景的治疗方法。
Colorectal cancer is the third most common malignancy worldwide, with 1.3 million new cases annually. Metastasis to the liver is a leading cause of mortality in these patients. In human liver, metastatic cancer cells must evade populations of liver-resident natural killer (NK) cells with potent cytotoxic capabilities. Here, we investigated how these tumors evade liver NK-cell surveillance. Tissue biopsies were obtained from patients undergoing resection of colorectal liver metastasis (CRLM, n = 18), from the tumor, adjacent tissue, and distal resection margin. The number and phenotype of liver-resident NKcells, at each site, were analyzed by flow cytometry. Tumor-conditioned media (TCM) was generated for cytokine and metabolite quantification and used to treat healthy liver-resident NK cells, isolated from donor liver perfusate during transplantation. Liver-resident NK cells were significantly depleted from CRLM tumors. Healthy liver-resident NK cells exposed to TCM underwent apoptosis in vitro, associated with elevated lactate. Tumor-infiltrating liver-resident NK cells showed signs of mitochondrial stress, which was recapitulated in vitro by treating liver-resident NK cells with lactic acid. Lactic acid induced apoptosis by decreasing the intracellular pH of NK cells, resulting in mitochondrial dysfunction that could be prevented by blocking mitochondrial ROS accumulation. CRLM tumors produced lactate, thus decreasing the pH of the tumor microenvironment. Liver-resident NK cells migrating toward the tumor were unable to regulate intracellular pH resulting in mitochondrial stress and apoptosis. Targeting CRLM metabolism provides a promising therapeutic approach to restoring local NK-cell activity and preventing tumor growth.