Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma

Abstract

BackgroundGlutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy.MethodsWe comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD.ResultsPatients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, “hot” immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells.ConclusionThis study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.

Unraveling the tumor immune microenvironment of lung adenocarcinoma using single-cell RNA sequencing

“…The prognostic markers and the indications for prognosis in these studies are summarized in Table 2 . 36 , 44 , 45 , 47 – 49 , 55 – 89 DEGs and their combined prognostic model were the most common types of prognostic markers in these studies. For example, one study identified nine cancer-specific DEGs (CBFA2T3, CR2, SEL1L3, TM6SF1, TSPAN32, ITGA6, MAPK11, RASA3, and TLR6) and established a prognostic risk model in combination with clinical factors.…”

“…The studies on therapeutic response and details of the markers are summarized in Table 3 . 40 , 44 , 57 , 61 , 64 , 69 , 75 , 76 , 78 , 81 , 82 , 86 , 88 , 89 , 91 – 99 Several DEGs have been found to predict patient response. In one study, four immune-related genes, including PTPRC, CCR2, SLAMF1, and HLA-DQA2 were identified as the signature for better outcomes.…”

New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication

“… 194 The researchers discovered that the tumor‐infiltrating T cells (especially CD8 T cell exhaustion and Treg suppression) presented the highest active levels of Gln metabolism among immune cells by building a quantitative system of Gln metabolism, which can be used to predict the prognosis and the immunotherapy efficacy including ICI and T cell adoptive therapy in lung cancer. 195 …”

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…Tex amino acid metabolism is generally impaired, but glutamine metabolism is more highly active than it is at other stages of the CD8+ TIL transition process. 88 Notably, the significant upregulation of glutamine metabolism, associated with the activation of the transforming growth factor‐β (TGF‐β) signalling pathway, leads to a reduction in the expression of the tissue‐resident marker CD103 on Texs and induces T‐cell apoptosis and impairment. 89 Nevertheless, in the colorectal cancer microenvironment, glutamine not only enhances CD8+ T‐cell glycolysis and lactate metabolism but also serves as an essential nutrient for cytokine synthesis.…”