The PD-L1 metabolic interactome intersects with choline metabolism and inflammation

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Metabolic Implications of Immune Checkpoint Proteins in Cancer

“…Chk-α is an enzyme that phosphorylates choline to phosphocholine, subsequently increasing choline metabolism and the availability of choline-containing compounds. PD-L1 and Chk-α have been shown to have an inverse relationship that impacts lipid metabolism and immunosuppression [ 88 ]. Targeting PD-L1 increased phosphocholine due to the increase in Chk-α, potentially providing precursors to support proliferation through membrane formation [ 88 ].…”

“…PD-L1 and Chk-α have been shown to have an inverse relationship that impacts lipid metabolism and immunosuppression [ 88 ]. Targeting PD-L1 increased phosphocholine due to the increase in Chk-α, potentially providing precursors to support proliferation through membrane formation [ 88 ]. However, when PD-L1 and Chk-α are targeted in combination, these changes were attenuated as no metabolic changes were observed [ 88 ].…”

“…Targeting PD-L1 increased phosphocholine due to the increase in Chk-α, potentially providing precursors to support proliferation through membrane formation [ 88 ]. However, when PD-L1 and Chk-α are targeted in combination, these changes were attenuated as no metabolic changes were observed [ 88 ]. Therefore, PD-L1 regulates cancer cell metabolism through Chk-α, and targeting both PD-L1 and Chk-α in combination may be beneficial to enhance antitumor immune cell surveillance to improve response to immune checkpoint blockade therapy.…”

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

“…Recently, a functional relationship between the immune checkpoint programmed cell death protein-1 (PD-1) and ChoKα has been established [176]. PD-L1 regulates metabolism through ChoKα, COX-2, and TGF-β, a new twist in the application of combinatorial therapies targeting both the immune checkpoints and modulation of critical enzymes involved in cancer metabolism.…”

The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy

“…For example, the relationship between VLCFA-containing lipids with ICI response via upregulation of peroxisome signaling in T-cells was indicated based on the integration of transcriptome data in TCGA with a metabolomics dataset from urological cancer patients [95]. In addition, comprehensive interpretation by nuclear magnetic resonance-based metabolomics, proteomic data, and TCGA provided choline kinase-α, cylcooxygenase-2, and transforming growth factor-β as promising options for combinatorial therapies based on ICIs [91].…”