PD-L1 stimulation can promote proliferation and survival of leukemic cells by influencing glucose and fatty acid metabolism in acute myeloid leukemia

Abstract

Background Leukemic cell metabolism plays significant roles in their proliferation and survival. These metabolic adaptations are under regulation by different factors. Programmed Death Ligand -1 (CD-274) is one of the immune checkpoint ligands that do not only cause the immune escape of cancer cells, but also have some intracellular effects in these cells. PD-L1 is overexpressed on leukemic stem cells and relates with poor prognosis of AML. In this study, we investigated effects of PD-L1 stimulation on critical metabolic pathways of glucose and fatty acid metabolisms that have important roles in proliferation and survival of leukemic cells. Methods After confirmation of PD-L1 expression by flow cytometry assay, we used recombinant protein PD-1 for stimulation of the PD-L1 on two AML cell lines, HL-60 and THP-1. Then we examined the effect of PD-L1 stimulation on glucose and fatty acid metabolism in cells at the genomic and metabolomic levels in a time dependent manner. We investigated expression changes of rate limiting enzymes of theses metabolic pathways (G6PD, HK-2, CPT1A, ATGL1 and ACC1) by qRT-PCR and also the relative abundance changes of free fatty acids of medium by GC. Results We identified a correlation between PD-L1 stimulation and both fatty acid and glucose metabolism. The PD-L1 stimulated cells showed an influence in the pentose phosphate pathway and glycolysis by increasing expression of G6PD and HK-2 (P value = 0.0001). Furthermore, PD-L1 promoted fatty acid β-oxidation by increasing expression of CPT1A (P value = 0.0001), however, their fatty acid synthesis was decreased by reduction of ACC1 expression (P value = 0.0001). Conclusion We found that PD-L1 can promote proliferation and survival of AML stem cells probably through some metabolic changes in leukemic cells. Pentose phosphate pathway that has a critical role in cell proliferation and fatty acids β-oxidation that promote cell survival, both are increased by PD-L1 stimulation on AML cells.

Scoparone attenuates PD-L1 expression in human breast cancer cells by MKP-3 upregulation

“…Furthermore, it is associated with cancer stem cell proliferation (Azuma et al 2008 ; Yang et al 2015 ). PD-L1 can enhance the proliferation and survival of acute myeloid leukemia cells by upregulating the pentose phosphate pathway, which is crucial for cell proliferation and the β -oxidation of fatty acids, which promotes cell survival (Soltani et al 2023 ). PD-L1 suppresses tumor autophagy by promoting basal mTORC1 signaling in melanoma and ovarian cancer models (Clark et al 2016 ).…”

YTHDF2-mediated circYAP1 drives immune escape and cancer progression through activating YAP1/TCF4-PD-L1 axis

“…PD-L1 promoted stem cell proliferation and survival through changes in glucose metabolism and fatty acid metabolism in leukemia cells. 38 In acute myeloid leukemia, PD-L1 activated the PI3K-AKT signaling pathway to regulate cell proliferation and apoptosis. 39 PD-L1 promoted invasion and metastasis in ovarian cancer.…”

The Association between Immune Checkpoint Proteins and Therapy Outcomes in Acute Myeloid Leukaemia Patients

“…Another option is an in-depth insight into additional pathways that could influence the response of leukemic cells to therapy with anti-PD-L1. Soltani et al suggested that certain metabolic pathways of leukemic cells that were affected by blockers of PD-L1, might be promising targets for novel drugs implemented additionally in ICI therapy [ 41 ].…”