Abstract
BackgroundHarnessing 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment
We focused on triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) because the outcomes of immune checkpoint inhibitor treatments in these cancers have yet to match the successes observed in melanoma and lung cancer [28, 29]
choline kinase-α (Chk-α) and PD-L1 expression are interactively related To identify the interactive relationship between choline kinase (Chk)-α and PD-L1, we used small interfering RNA (siRNA) to downregulate Chk-α and PD-L1 in TNBC MDA-MB-231 and SUM-149 cells, and in Pa09C and Pa20C human PDAC cells [32]
Summary
Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. Along with the expanded interest in blocking immune checkpoints for cancer immunotherapy, recent studies have identified the important role of metabolism in immune suppression and the tumor immune microenvironment (TIME) [2, 3]. Cancer cells can create an immune-suppressive microenvironment through metabolic reprogramming, by changing the metabolic profile of the tumor microenvironment (TME) and exerting high metabolic stress on tumorinfiltrating immune cells that lead to their functional inactivation [4,5,6,7]. PD-L1 levels are, directly modulated in cancer cells by lactate [12], arginine [13], or glutamate [14], and in immune cells by arginine [13] and glutamine [15]. Metabolic inhibitors of the glutamate, glutamine, and arginine pathways are being evaluated in clinical trials in combination with immune checkpoint inhibitors with promising outcomes [6]
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