bims-meluca 2022-09-04 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–09–04
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma.
Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer.
Significant metabolic alterations in non-small cell lung cancer patients by epidermal growth factor receptor-targeted therapy and PD-1/PD-L1 immunotherapy.
Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy.
Signature and Molecular Mechanism of Mitochondrial Energy Metabolism Pathway-Related Genes in Lung Adenocarcinoma.
Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.
IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.

Front Immunol. 2022 ;13 960738

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

Jichang Liu, Hongchang Shen, Wenchao Gu, Haotian Zheng, Yadong Wang, Guoyuan Ma, Jiajun Du.

   Background: Glutamine (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.
Methods: We 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.
Results: Patients 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.
Conclusion: This 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.

Keywords:  EphB2; glutamine metabolism; immunotherapy; lung adenocarcinoma; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.960738
Open Life Sci. 2022 ;17(1): 881-892

Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer.

Jing Li, Yun Guan, Rongrong Zhu, Yang Wang, Huaguang Zhu, Xin Wang.

  Early-stage non-small cell lung cancer (NSCLC) patients are at substantial risk of poor prognosis. We attempted to develop a reliable metabolic gene-set-based signature that can predict prognosis accurately for early-stage patients. Least absolute shrinkage and selection operator method Cox regression models were performed to filter the most useful prognostic genes, and a metabolic gene-set-based signature was constructed. Forty-two metabolism-related genes were finally identified, and with specific risk score formula, patients were classified into high-risk and low-risk groups. Overall survival was significantly different between the two groups in discovery (HR: 5.050, 95% CI: 3.368-7.574, P < 0.001), internal validation series (HR: 6.044, 95% CI: 3.918-9.322, P < 0.001), GSE30219 (HR: 2.059, 95% CI: 1.510-2.808, P < 0.001), and GSE68456 (HR: 2.448, 95% CI: 1.723-3.477, P < 0.001). Survival receiver operating characteristic curve at the 5 years suggested that the metabolic signature (area under the curve [AUC] = 0.805) had better prognostic accuracy than any other clinicopathological factors. Further analysis revealed the distinct differences in immune cell infiltration and tumor purity reflected by an immune and stromal score between high- and low-risk patients. In conclusion, the novel metabolic signature developed in our study shows robust prognostic accuracy in predicting prognosis for early-stage NSCLC patients and may function as a reliable marker for guiding more effective immunotherapy strategies.

Keywords:  biomarker; immune infiltration; lung cancer; metabolism; overall survival

DOI:  https://doi.org/10.1515/biol-2022-0091
Front Pharmacol. 2022 ;13 949745

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

Chen Yan, Dan Wu, Lingling Gan, Jun Wang, Wenyu Yang, Bei Xu.

  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.

Keywords:  PD-1/PD-L1 immunotherapy; epidermal growth factor receptor-targeted therapy; non-small cell lung cancer; tumor metabolic reprogramming; untargeted metabolomics

DOI:  https://doi.org/10.3389/fphar.2022.949745
Front Immunol. 2022 ;13 906815

Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy.

Linfang Wu, Daquan Wang, Yanhua Chen, Mingmin Qian, Xin Xu, Tao Zhang, Nan Bi, Luhua Wang.

   Objective: High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.
Materials and methods: Systemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.
Results: In 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).
Conclusion: Favorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.

Keywords:  immune suppression; indoleamine 2,3-dioxygenase (IDO); non-small cell lung cancer (NSCLC); radio-resistance; radiotherapy

DOI:  https://doi.org/10.3389/fimmu.2022.906815
Dis Markers. 2022 ;2022 3201600

Signature and Molecular Mechanism of Mitochondrial Energy Metabolism Pathway-Related Genes in Lung Adenocarcinoma.

Jiayuan Liu, Feng Zhang, Jinlong Zhong, Zhi Zheng.

Objective: The mitochondrial energy metabolic pathway (MEMP) is the primary energy metabolism of tumor cells, and its disruption may promote cancer emergence, spreading, and immune escape. However, there is a lack of studies to determine the relationship between relevant functional mechanisms and lung adenocarcinoma (LUAD) prognosis.
Methods: Gene set enrichment analysis (GSEA) was employed to determine MEMP pathway-related genes. Then, a prognostic model was created using the MEMP key genes that were found by LASSO-Cox regression analysis. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provided the training and validation sets. Furthermore, the infiltration of immune cells was examined by ssGSEA. Finally, a screening of candidate therapeutic compounds for LUAD patients was performed using DrugBank, Protein Data Bank (PDB), and AutoDock Vina databases.
Results: First, 266 MEMP pathway-related genes that exhibited aberrant activity in tumors were identified. Then, 19 MEMP key genes were used to build a prognostic model, which can successfully predict the survival rates of LUAD patients after 1, 3, and 5 years, respectively. The Kaplan-Meier curve showed that patients in the high-risk group had considerably lower survival outcomes than those in the low-risk group. Furthermore, it was discovered that the high-risk group had the majority of activated T cells, while the low-risk group tended to have more other activated immune cells. The majority of immunological checkpoints expressed themselves more strongly in the high-risk group as well. Finally, 11 prospective medication small molecules were obtained from the projected potential therapeutic drugs, with DB0980 being regarded as the most promising of them for the treatment of LUAD.
Conclusion: This current study developed reliable prognostic signature, called MEMP score, which provides new guidance for prognostic assessment, immunotherapy, and drug development in LUAD. Thereby, DB0980 appears to be the most likely approach for the treatment of LUAD.

DOI: https://doi.org/10.1155/2022/3201600
Front Endocrinol (Lausanne). 2022 ;13 988295

Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.

Yifei Zhu, Xinyan Li, Lei Wang, Xiwei Hong, Jie Yang.

  It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.

Keywords:  Tumor microenvironment; cancer-associated fibroblasts; immune cells; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.3389/fendo.2022.988295
Oncoimmunology. 2022 ;11(1): 2116844

IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.

Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, Jean-Ehrland Ricci.

  IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.

Keywords:  Cancer; IRE1α; RIDD; UPR; XBP1s; anti-cancer immunosurveillance; apoptosis

DOI:  https://doi.org/10.1080/2162402X.2022.2116844