bims-meluca 2023-02-05 papers

Front Oncol. 2022 ;12 1025046

Metabolomics profiling in prediction of chemo-immunotherapy efficiency in advanced non-small cell lung cancer.

Lihong Mei, Zhihua Zhang, Xushuo Li, Ying Yang, Ruixue Qi.

Background: To explore potential metabolomics biomarker in predicting the efficiency of the chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC).
Methods: A total of 83 eligible patients were assigned to receive chemo-immunotherapy. Serum samples were prospectively collected before the treatment to perform metabolomics profiling analyses under the application of gas chromatography mass spectrometry (GC-MS). The key metabolites were identified using projection to latent structures discriminant analysis (PLS-DA). The key metabolites were used for predicting the chemo-immunotherapy efficiency in advanced NSCLC patients.
Results: Seven metabolites including pyruvate, threonine, alanine, urea, oxalate, elaidic acid and glutamate were identified as the key metabolites to the chemo-immunotherapy response. The receiver operating characteristic curves (AUC) were 0.79 (95% CI: 0.69-0.90), 0.60 (95% CI: 0.48-0.73), 0.69 (95% CI: 0.57-0.80), 0.63 (95% CI: 0.51-0.75), 0.60 (95% CI: 0.48-0.72), 0.56 (95% CI: 0.43-0.67), and 0.67 (95% CI: 0.55-0.80) for the key metabolites, respectively. A binary logistic regression was used to construct a combined biomarker model to improve the discriminating efficiency. The AUC was 0.86 (95% CI: 0.77-0.94) for the combined biomarker model. Pathway analyses showed that urea cycle, glucose-alanine cycle, glycine and serine metabolism, alanine metabolism, and glutamate metabolism were the key metabolic pathway to the chemo-immunotherapy response in patients with advanced NSCLC.
Conclusion: Metabolomics analyses of key metabolites and pathways revealed that GC-MS could be used to predict the efficiency of chemo-immunotherapy. Pyruvate, threonine, alanine, urea, oxalate, elaidic acid and glutamate played a central role in the metabolic of PD patients with advanced NSCLC.

Keywords: GC-MS; biomarker; chemo-immunotherapy; metabolomics; non-small cell lung cancer

DOI: https://doi.org/10.3389/fonc.2022.1025046

Surg Today. 2023 Jan 31.

Clinical significance of the preoperative prognostic nutritional index on age/comorbidity burdens in patients with resectable non-small cell lung cancer.

Mamoru Takahashi, Hironobu Tokumasu, Sachiko Ota, Harutaro Okada, Akihiro Aoyama.

PURPOSE: Objective nutritional scoring systems using preoperative blood samples have shown the potential to predict the postoperative outcomes of patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether the prognostic impact depends on age and comorbid burdens. We conducted this study to validate the impact of preoperative nutritional status, stratified with age and comorbidity.
METHODS: We reviewed the preoperative prognostic nutritional index (PNI) and postoperative outcomes of 713 consecutive patients with completely resected NSCLC.
RESULTS: We identified the optimal cutoff values of the PNI as 46. Significantly higher postoperative complication rates and worse survival rates were observed in the low PNI (≤ 46) group, regardless of age/comorbidity burdens. Multivariate analysis showed that a low PNI (≤ 46) was an independent prognostic factor for poor overall survival (hazard ratio: 2.5). A matched-pair analysis gave consistent results, showing that a low PNI (≤ 46) was an independent prognostic factor for poor overall survival (OS; hazard ratio: 1.8) and recurrence-free survival (RFS; hazard ratio: 1.6).
CONCLUSION: Nutritional status, indexed by the PNI, is a strong prognostic factor for the postoperative outcomes of patients undergoing curative resection for NSCL, regardless of age/comorbidity burdens.

Keywords: Age-adjusted Charlson comorbidity index; Non-small cell lung cancer; Prognostic nutritional index

DOI: https://doi.org/10.1007/s00595-023-02650-8

Dis Markers. 2023 ;2023 9292536

High Expression of DLGAP5 Indicates Poor Prognosis and Immunotherapy in Lung Adenocarcinoma and Promotes Proliferation through Regulation of the Cell Cycle.

Xiaolong Tang, Honghong Zhou, Yongshuo Liu.

Background: Lung adenocarcinoma (LUAD) is one of the most common types of cancer in the respiratory system, with a high mortality and recurrence rate. The role of disc large-associated protein 5 (DLGAP5) in LUAD progression and tumor microenvironment (TME) remains unclear. This study is aimed at revealing the functional role of DLGAP5 in LUAD based on bioinformatics analysis and experimental validation.
Methods: Differential expression analysis, protein-protein interaction (PPI) network, and Cox regression analysis were applied to screen potential prognostic biomarkers. The mRNA and protein levels of DLGAP5 were analyzed using The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) databases. The CCK-8 and colony formation assays were performed to assess the effect of DLGAP5 on cell proliferation. RNA sequencing (RNA-seq) and enrichment analyses were utilized to explore the biological functions of DLGAP5. Furthermore, flow cytometry was used to explore the role of DLGAP5 on the cell cycle. The ssGSEA algorithm in the R package "GSVA" was applied to quantify immune infiltrating cells, and the tumor immune dysfunction and exclusion (TIDE) algorithm was used to predict the efficacy of immunotherapy. Moreover, analyses using the cBioPortal and MethSurv databases were performed to evaluate the mutation and methylation of DLGAP5, respectively. Finally, the prognostic value of DLGAP5 was estimated using the TCGA and the Gene Expression Omnibus (GEO) databases. The nomogram model was constructed using the TCGA-LUAD cohort and evaluated by adopting calibration curves, time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis (DCA).
Results: DLGAP5 mRNA and protein abundance were significantly elevated in LUAD, and knockdown of DLGAP5 remarkably suppressed lung cancer cell proliferation through induction of cell cycle G1 arrest. In addition, DLGAP5 expression was positively correlated with Th2 cells and negatively correlated with B cells, T follicular helper cells, and mast cells. LUAD patients with high DLGAP5 expression may be resistant to immunotherapy. Hypermethylation levels of the cg23678254 site of DLGAP5 or its enhanced expression were unfavorable for the survival of LUAD patients. Meanwhile, DLGAP5 expression was associated with TNM stages, tumor status, and therapy outcome. Notably, the prognostic model constructed based on DLGAP5 expression exhibited great predictive capability, which was promising for clinical applications.
Conclusion: DLGAP5 promotes lung cancer cell proliferation through regulation of the cell cycle and is associated with multiple immune infiltrating cells. Furthermore, DLGAP5 predicts poor prognosis and response to immunotherapy in lung adenocarcinoma.

DOI: https://doi.org/10.1155/2023/9292536

Cancer Discov. 2023 Jan 30. pii: CD-22-0805. [Epub ahead of print]

LKB1-dependent regulation of TPI1 creates a divergent metabolic liability between human and mouse lung adenocarcinoma.

Benjamin D Stein, John R Ferrarone, Eric E Gardner, Jae Won Chang, David Wu, Pablo E Hollstein, Roger J Liang, Min Yuan, Qiuying Chen, John S Coukos, Miriam Sindelar, Bryan Ngo, Steven S Gross, Reuben J Shaw, Chen Zhang, John M Asara, Raymond E Moellering, Harold Varmus, Lewis C Cantley.

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD) and activating mutations frequently co-occur with loss-of-function mutations in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered co-mutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the Salt Inducible Kinases (SIKs) in an LKB1-dependent manner, modulating flux between completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue which can be oxidized to alter TPI1 activity without a need for SIKs or LKB1. Our findings suggest this metabolic flexibility is critical in rapidly growing cells with KRAS and TP53 mutations, explaining why loss of LKB1 creates a liability in these tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0805

Cancer Immunol Immunother. 2023 Feb 04.

The role of spatial interplay patterns between PD-L1-positive tumor cell and T cell in recurrence of locally advanced non-small cell lung cancer.

Liying Yang, Wei Zhang, Jujie Sun, Guanqun Yang, Siqi Cai, Fenghao Sun, Ligang Xing, Xiaorong Sun.

PURPOSE: To explore the relationship between the spatial interaction of programmed death-ligand 1(PD-L1)-positive tumor cell and T cell with specific functions and the recurrence of non-small cell lung cancer (NSCLC) and optimize prognostic stratification.
MATERIALS AND METHODS: This study retrospectively included 104 patients with locally advanced NSCLC who underwent radical surgery. Tissue microarrays were constructed including tumor center (TC) and invasion margin (IM), and CK/CD4/CD8/PD-L1/programmed death-1 (PD-1) was labeled using multiplex immunofluorescence to decipher the counts and spatial distribution of tumor cells and T cells. The immune microenvironment and recurrence stratification were characterized using the Mann-Whitney U test and Cox proportional hazards model.
RESULT: Compared with the IM, the proportion of tumor cells (especially PD-L1+) was increased in the TC, while T cells (especially PD-1+) were decreased. An increase in TC PD-1+ CD8 T cells promoted relapse (HR = 2.183), while PD-L1+ tumor cells alone or in combination with T cells had no predictive value for relapse. In addition, in both TC and IM, CD8 were on average closer to PD-L1+ tumor cells than CD4, especially exhausted CD8. The effective density and percentage of PD-1+ CD4 T cells interacting with PD-L1+ tumor cells in the IM were both associated with recurrence, and the HRs increased sequentially (HRs were 2.809 and 4.063, respectively). Patients with low PD-1+CD4 count combined high PD-1+CD4 effective density showed significantly poorer RFS compared to those with high PD-1+CD4 count combined low PD-1+CD4 effective density, in both the TC and IM regions (HRs were 5.810 and 8.709, respectively).
CONCLUSION: Assessing the relative spatial proximity of PD-1/PD-L1 contributes to a deeper understanding of tumor immune escape and generates prognostic information in locally advanced NSCLC patients.

Keywords: Non-small cell lung cancer; Prognosis; Programmed death-1; Programmed death-ligand 1; Spatial interaction

DOI: https://doi.org/10.1007/s00262-023-03380-z

Front Oncol. 2022 ;12 1023833

A signature-based classification of lung adenocarcinoma that stratifies tumor immunity.

Xun Zhang, Dizhi Jiang, Shunjia Li, Xinyu Zhang, Wendi Zheng, Bo Cheng.

Background: Immune-related subgroup classification in immune checkpoint blockade (ICB) therapy is largely inconclusive in lung adenocarcinoma (LUAD).
Materials and methods: First, the single-sample Gene Set Enrichment Analysis (ssGSEA) and K-means algorithms were used to identify immune-based subtypes for the LUAD cohort based on the immunogenomic profiling of 29 immune signatures from The Cancer Genome Atlas (TCGA) database (n = 504). Second, we examined the prognostic and predictive value of immune-based subtypes using bioinformatics analysis. Survival analysis and additional COX proportional hazards regression analysis were conducted for LUAD. Then, the immune score, tumor-infiltrating immune cells (TIICs), and immune checkpoint expression of the three subtypes were analyzed. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) of the differentially expressed genes (DEGs) between three immune-based subtypes were subsequently analyzed for functional enrichment pathways.
Result: A total of three immune-based subtypes with distinct immune signatures have been identified for LUAD and designated as cluster 1 (C1), cluster 2 (C2), and cluster 3 (C3). Patients in C3 had higher stromal, immune, and ESTIMATE scores, whereas those in C1 had the opposite. Patients in C1 had an enrichment of macrophages M0 and activation of dendritic cells, whereas tumors in C3 had an enrichment of CD8+ T cells, activation of CD4+ memory T cells, and macrophages M1. C3 had a higher immune cell infiltration and a better survival prognosis than other subtypes. Furthermore, patients in C3 had higher expression levels of immune checkpoint proteins such as PD-L1, PD1, CTLA4, LAG3, IDO1, and HAVCR2. No significant differences were found in cluster TMB scores. We also found that immune-related pathways were enriched in C3.
Conclusion: LUAD subtypes based on immune signatures may aid in the development of novel treatment strategies for LUAD.

Keywords: immunophenotypes; immunotherapy; lung adenocarcinoma; prognostic model; tumor-infiltrating immune cells

DOI: https://doi.org/10.3389/fonc.2022.1023833