Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and the expression of the immune checkpoint PD-L1. We used small interfering RNA to downregulate Chk-α, PD-L1, or both in two triple-negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic, and metabolomic levels. The findings were compared with the results obtained by the analysis of public data from The Cancer Genome Atlas Program. We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic, and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2, and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.

中文翻译：

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PD-L1代谢相互作用组与胆碱代谢和炎症相交

通过使用免疫检查点抑制剂来利用免疫系统的力量，已导致癌症治疗方面一些最令人兴奋的进展。但是，这种方法的全部潜力尚未完全实现，可以用于治疗许多癌症，例如胰腺癌和乳腺癌。癌症代谢会影响癌症进展的许多方面，包括免疫监视。对癌症新陈代谢如何直接影响免疫检查点的进一步理解可能会进一步优化免疫疗法。因此，我们首次研究了在大多数癌症中观察到的一种酶胆碱激酶-α（Chk-α）的过表达与免疫检查点PD-L1的表达之间的关系。我们使用小的干扰RNA来下调Chk-α，PD-L1，或在两个三阴性人类乳腺癌细胞系（MDA-MB-231和SUM-149）和两个人类胰腺导管腺癌细胞系（Pa09C和Pa20C）中同时使用。在基因组，蛋白质组和代谢组学水平研究了下调的影响。将研究结果与通过分析癌症基因组图谱计划的公共数据获得的结果进行了比较。我们在基因组，蛋白质组学和代谢组学水平上确定了Chk-α和PD-L1之间的逆相关性。我们还发现，前列腺素-内过氧化物合酶2（COX-2）和转化生长因子β（TGF-β）在这种关系中起着重要作用。我们通过分析癌症基因组图谱计划的数据独立确认了人类癌症中的这种关系。我们的数据确定了PD-L1在癌细胞代谢重编程中未知的作用，并揭示了Chk-α下调的免疫抑制性PD-L1效应增加。这些数据表明PD-L1对代谢的调节可能是通过Chk-α，COX-2和TGF-β介导的。这些发现提供了新的见解，可应用于针对免疫检查点和癌症代谢的组合疗法的合理设计。