Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: a pilot cohort study for developing a prognostic multivariate model.

Background: Amino acid metabolism is essential for tumor cell proliferation and regulation of immune cell function. However, the clinical significance of free amino acids (plasma-free amino acids (PFAAs)) and tryptophan-related metabolites in plasma has not been fully understood in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors.
Methods: We conducted a single cohort observational study. Peripheral blood samples were collected from 53 patients with NSCLC before treatment with PD-1 (Programmed cell death-1) inhibitors. The plasma concentrations of 21 PFAAs, 14 metabolites, and neopterin were measured by liquid chromatography-mass spectrometry. Using Cox hazard analysis with these variables, a multivariate model was established to stratify patient overall survival (OS). Gene expression in peripheral blood mononuclear cells (PBMCs) was compared between the high-risk and low-risk patients by this multivariate model.
Results: On Cox proportional hazard analysis, higher concentrations of seven PFAAs (glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan) as well as lower concentrations of three metabolites (3h-kynurenine, anthranilic acid, and quinolinic acid) and neopterin in plasma were significantly correlated with better OS (p<0.05). In particular, the multivariate model, composed of a combination of serine, glycine, arginine, and quinolinic acid, could most efficiently stratify patient OS (concordance index=0.775, HR=3.23, 95% CI 2.04 to 5.26). From the transcriptome analysis in PBMCs, this multivariate model was significantly correlated with the gene signatures related to immune responses, such as CD8 T-cell activation/proliferation and proinflammatory immune responses, and 12 amino acid-related genes were differentially expressed between the high-risk and low-risk groups.
Conclusions: The multivariate model with PFAAs and metabolites in plasma might be useful for stratifying patients who will benefit from PD-1 inhibitors.
Competing Interests: Competing interests: KA reports receiving personal fees from AstraZeneka, MSD, Bristol Myers Squibb, Ono Pharmaceutical and Chugai Pharmaceutical. HI reports receiving personal fees from AstraZeneka, KyowaKirin, AMCO, Ono Pharmaceutical, and Chugai Pharmaceutical. TTa reports receiving personal fees from AstraZeneka, Ono Pharmaceutical, and Chugai Pharmaceutical. KM reports receiving personal fees from AstraZeneka, MSD, Taiho, Boehringer Ingelheim, Ono Pharmaceutical, and Chugai Pharmaceutical. TS reports receiving personal fees from Bristol Myers Squibb and Chugai Pharmaceutical. TTo, YK, SKa, SKi, and AI are employees of Ajinomoto Co. The remaining authors have no conflicts of interest to disclose.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)