Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy

Abstract

Background: Cancer-related deaths are primarily attributable to lung cancer, of which non-small cell lung cancer (NSCLC) is the most common type. Molecular targeting therapy and antitumor immunotherapy have both made great strides in the treatment of NSCLC, but their underlying mechanisms remain unclear, especially from a metabolic perspective.Methods: Herein, we used a nontargeted metabolomics approach based on liquid chromatography-mass spectrometry to analyze the metabolic response of NSCLC patients to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) or PD-1/PD-L1 inhibitors. Multiple analyses, including principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) and pathway analysis, were used for metabolic data analysis. Additionally, differential metabolites were analysed and identified by publically available and integrated databases.Results: After treatment with EGFR-TKIs or PD-1/PD-L1 inhibitors, glutamate/glutamine, phenylalanine, n-acetyl-l-leucine, n-acetyl-d-tryptophan, D-n-valine, arachidonic acid, and linoleic acid levels were significantly increased in patients with NSCLC, whereas carnitine, stearyl carnitine, palmitoyl carnitine, linoleic carnitine, and palmitic acid levels were markedly decreased. Compared with newly diagnosed, untreated patients, there were three shared metabolic pathways (phenylalanine metabolism, glycerophospholipid metabolism, and D-glutamine and D-glutamate metabolism) in the EGFR-TKIs or PD-1/PD-L1 inhibitor-treated groups, all of which were related to lipid and amino acid metabolism. Moreover, there were significant differences in lipid metabolism (glycerophospholipid metabolism and phosphatidylinositol signaling) and amino acid metabolism (tryptophan metabolism) between the EGFR-TKI and PD-1/PD-L1 inhibitor groups.Conclusion: Our results show that EGFR-TKIs and PD-1/PD-L1 inhibitors induce changes in carnitine, amino acids, fatty acids, and lipids and alter related metabolic pathways in NSCLC patients. Endogenous metabolism changes occur due to drug action and might be indicative of antitumor therapeutic effect. These findings will provide new clues for identifying the antitumor mechanism of these two treatments from the perspective of metabolism.

A fatty acid-rich fraction of an endolichenic fungus Phoma sp. suppresses immune checkpoint markers via AhR/ARNT and ESR1

“…Another reported that oleic acid regulates inflammation, as well as various immunomodulators, through Th2/GATA-3 and interleukin-17/RORγt [ 48 ]. Inhibition of PD-L1, EGFR, and tyrosine kinases by palmitic acid has been reported [ 49 ]. Although fatty acids are commonly used in nano-emulsions, we showed that a derivative of palmitic acid improved T cell immune responses by inhibiting PD-L1 [ 50 ].…”

Metabolomic profile of secondary hyperparathyroidism in patients with chronic kidney disease stages 3–5 not receiving dialysis

“…The mobile phase was composed of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), the flow rate was 0.30 mL/min and the column temperature was 30°C. The UPLC-MS/MS analytical conditions were as previously described ( 18 ). For MS, both positive and negative electrospray ionization (ESI) modes were used.…”

“…Analysis was performed as previously described ( 18 ). Principal component analysis and partial least square discriminant analysis (PLS-DA) were used to investigate data clustering trends and differences among the groups.…”

The impact of concurrent bacterial lung infection on immunotherapy in patients with non-small cell lung cancer: a retrospective cohort study

“…The inflammatory and immune microenvironments induced by BLI are closely associated to the development and progression of NSCLC (Takada et al, 2022;Tang et al, 2023). Immunotherapy has made significant strides in the treatment of NSCLC in recent years, particularly with ICIs represented by inhibitors of the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway, which have substantially enhanced NSCLC patients' survival and prognosis (Yan et al, 2022;You et al, 2023). However, a substantial number of patients do not benefit from ICIs, and there is a risk of adverse effects related to immunotherapy, especially the incidence of checkpoint inhibitor-related pneumonia (CIP) in NSCLC patients, which is significantly higher than in patients with other types of tumors (Suresh et al, 2019;Cao et al, 2022c).…”