Department of Surgery, University of Miami, Miami, Florida.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, Florida.
Cancer Res. 2021 Aug 1;81(15):4001-4013. doi: 10.1158/0008-5472.CAN-20-2562. Epub 2021 May 14.
In pancreatic cancer, the robust fibroinflammatory stroma contributes to immune suppression and renders tumors hypoxic, altering intratumoral metabolic pathways and leading to poor survival. One metabolic enzyme activated during hypoxia is lactate dehydrogenase A (LDHA). As a result of its promiscuous activity under hypoxia, LDHA produces L-2 hydroxyglutarate (L-2HG), an epigenetic modifier, that regulates the tumor transcriptome. However, the role of L-2HG in remodeling the pancreatic tumor microenvironment is not known. Here we used mass spectrometry to detect L-2HG in serum samples from patients with pancreatic cancer, comprising tumor cells as well as stromal cells. Both hypoxic pancreatic tumors as well as serum from patients with pancreatic cancer accumulated L-2HG as a result of promiscuous activity of LDHA. This abnormally accumulated L-2HG led to H3 hypermethylation and altered gene expression, which regulated a critical balance between stemness and differentiation in pancreatic tumors. Secreted L-2HG inhibited T-cell proliferation and migration, suppressing antitumor immunity. In a syngeneic orthotopic model of pancreatic cancer, inhibition of LDH with GSK2837808A decreased L-2HG, induced tumor regression, and sensitized tumors to anti-PD1 therapy. In conclusion, hypoxia-mediated promiscuous activity of LDH produces L-2HG in pancreatic tumor cells, regulating the stemness-differentiation balance and contributing to immune evasion. Targeting LDH can be developed as a potential therapy to sensitize pancreatic tumors to checkpoint inhibitor therapy. SIGNIFICANCE: This study shows that promiscuous LDH activity produces L-2HG in pancreatic tumor and stromal cells, modulating tumor stemness and immune cell function and infiltration in the tumor microenvironment.
在胰腺癌中，强健的纤维炎症基质有助于免疫抑制，并使肿瘤缺氧，改变肿瘤内代谢途径，导致预后不良。一种在缺氧时被激活的代谢酶是乳酸脱氢酶 A（LDHA）。由于其在缺氧下的混杂活性，LDHA 产生 L-2 羟戊酸（L-2HG），一种表观遗传修饰物，调节肿瘤转录组。然而，L-2HG 在重塑胰腺肿瘤微环境中的作用尚不清楚。在这里，我们使用质谱法检测了来自胰腺癌患者的血清样本中的 L-2HG，这些样本包含肿瘤细胞和基质细胞。由于 LDHA 的混杂活性，缺氧胰腺肿瘤以及来自胰腺癌患者的血清都积累了 L-2HG。这种异常积累的 L-2HG 导致 H3 过度甲基化和基因表达改变，调节了胰腺肿瘤中干性和分化之间的关键平衡。分泌的 L-2HG 抑制 T 细胞增殖和迁移，抑制抗肿瘤免疫。在胰腺癌的同基因原位模型中，用 GSK2837808A 抑制 LDH 可减少 L-2HG，诱导肿瘤消退，并使肿瘤对抗 PD1 治疗敏感。总之，缺氧介导的 LDHA 混杂活性在胰腺肿瘤细胞中产生 L-2HG，调节干性-分化平衡，并有助于免疫逃逸。靶向 LDH 可作为一种潜在的治疗方法，使胰腺肿瘤对检查点抑制剂治疗敏感。意义：本研究表明，混杂的 LDH 活性在胰腺肿瘤和基质细胞中产生 L-2HG，调节肿瘤干性和免疫细胞功能以及肿瘤微环境中的浸润。
