Pacheco-Torres Jesus, Penet Marie-France, Mironchik Yelena, Krishnamachary Balaji, Bhujwalla Zaver M
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Rm 208C Traylor Building, Baltimore, MD, 21205, USA.
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Cancer Metab. 2021 Feb 19;9(1):10. doi: 10.1186/s40170-021-00245-w.
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.
通过使用免疫检查点抑制剂来利用免疫系统的力量，已在癌症治疗领域带来了一些最令人振奋的进展。然而，这种方法在治疗许多癌症（如胰腺癌和乳腺癌）方面的全部潜力尚未得到充分实现。癌症代谢会影响癌症进展的许多方面，包括免疫监视。对癌症代谢如何直接影响免疫检查点的更深入理解，可能会使免疫疗法得到进一步优化。因此，我们首次研究了在大多数癌症中都存在的胆碱激酶-α（Chk-α）过表达与免疫检查点PD-L1表达之间的关系。
我们使用小干扰RNA下调两种三阴性人乳腺癌细胞系（MDA-MB-231和SUM-149）以及两种人胰腺导管腺癌细胞系（Pa09C和Pa20C）中的Chk-α、PD-L1或两者。在基因组、蛋白质组和代谢组水平上研究了下调的效果。将这些发现与通过分析癌症基因组图谱计划的公开数据所获得的结果进行了比较。
我们在基因组、蛋白质组和代谢组水平上确定了Chk-α与PD-L1之间存在反向依赖性。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）在这种关系中起重要作用。我们通过分析癌症基因组图谱计划的数据，在人类癌症中独立证实了这种关系。
我们的数据确定了PD-L1在癌细胞代谢重编程中以前未知的作用，并揭示了Chk-α下调对PD-L1的免疫抑制增强作用。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。这些观察结果提供了新的见解，可应用于针对免疫检查点和癌症代谢的联合疗法的合理设计。
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