bims-meluca 2023-09-03 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–09–03
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Baseline serum tumor markers predict the survival of patients with advanced non-small cell lung cancer receiving first-line immunotherapy: a multicenter retrospective study.
Survival and soluble immune mediators of immune checkpoint inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer.
An Investigation of the Relationship Between 18F-FDG PET/CT Parameters of Primary Tumors and Lymph Node Metastasis in Resectable Non-small Cell Lung Cancer.
Lysosome-related genes: A new prognostic marker for lung adenocarcinoma.
System analysis based on glutamine catabolic-related enzymes identifies GPT2 as a novel immunotherapy target for lung adenocarcinoma.
Exosome nanovesicles as potential biomarkers and immune checkpoint signaling modulators in lung cancer microenvironment: recent advances and emerging concepts.
Smoking Status at Time of Diagnosis Affects the Efficacy of Anti-PD-1/L1 Therapy in Patients With Advanced NSCLC.
Location of CD39+ T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer.

BMC Cancer. 2023 Aug 30. 23(1): 812

Baseline serum tumor markers predict the survival of patients with advanced non-small cell lung cancer receiving first-line immunotherapy: a multicenter retrospective study.

Jian Huang, Yi Xiao, Yubin Zhou, Huiyin Deng, Zihao Yuan, Longyan Dong, Jun Lan, Xiane Li, Gaijiao Liu, Hao Hu, Shaohong Huang, Xiongwen Yang.

   BACKGROUND: This study aimed to investigate the association between baseline serum tumor markers (STMs) (carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], cytokeratin-19 fragment [CYFRA21-1], carbohydrate antigen 19-9 [CA19-9], and carbohydrate antigen 125 [CA125]) and the efficacy of first-line immunotherapy in patients with advanced non-small cell lung cancer.
METHODS: This multicenter retrospective study evaluated patients who received first-line immunotherapy between July 2017 and July 2022. The endpoints were progression-free survival (PFS) and overall survival (OS), as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. We divided the patients into three groups based on STM levels: Group A ≥ threefold upper limit of normal, threefold upper limit of normal > Group B > upper limit of normal, and Group C ≤ upper limit of normal.
RESULTS: In total, 716 patients were included in this study. In Cox proportional hazards analyses, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung adenocarcinoma (LUAD). Except for CA19-9 level, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung squamous carcinoma (LUSC). Except for CEA and CA19-9 levels, the levels in Group A were independently associated with inferior PFS and OS in patients with LUAD and LUSC.
CONCLUSIONS: Serum CEA, NSE, CYFRA21-1, and CA125 levels can predict PFS and OS in patients with LUAD and LUSC, and serum CA19-9 levels can predict PFS and OS in patients with LUAD. The higher the serum NSE, CYFRA21-1, and CA125 levels, the worse the PFS and OS in patients with LUAD and LUSC. In addition, the higher the serum CA19-9 level, the worse the OS in patients with LUAD.

Keywords:  Baseline serum tumor markers; Immunotherapy; Non-small cell lung cancer; Overall survival; Progression-free survival

DOI:  https://doi.org/10.1186/s12885-023-11312-4
Lung Cancer. 2023 Aug 20. pii: S0169-5002(23)00889-9. [Epub ahead of print]184 107351

Survival and soluble immune mediators of immune checkpoint inhibitor-induced interstitial lung disease in patients with non-small cell lung cancer.

Daiki Murata, Koichi Azuma, Kenta Murotani, Norikazu Matsuo, Goushi Matama, Takaaki Tokito, Tetsuro Sasada, Tomoaki Hoshino.

   BACKGROUND: Immune checkpoint inhibitor-related interstitial lung disease (ICI-ILD) is a serious adverse event frequently observed in patients with non-small cell lung cancer (NSCLC). We investigated the clinical effects and mechanism of action of ICI-ILD in NSCLC patients treated with ICI.
METHODS: We retrospectively screened patients with advanced or recurrent NSCLC who received PD-1/PD-L1 inhibitor monotherapy and examined the prognostic impact of ICI-ILD. In addition, we analyzed the levels of 72 different soluble immune mediators in pre-treatment plasma to explore possible mechanisms associated with the development of ICI-ILD. Furthermore, the relationships between soluble immune mediators associated with ICI-ILD development and survival were analyzed.
RESULTS: Of 141 patients with NSCLC, 25 (17.7%) developed ICI-ILD. Logistic regression analysis revealed that pre-treatment CXCL9, MMP-1, IL-6, and IL-19 levels were associated with ICI-ILD development. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between patients with or without ICI-ILD. In patients with ICI-ILD, patients with lower grade ICI-ILD had better OS than those with higher-grade ICI-ILD. In ICI-ILD patients, there was a trend for patients with lower-grade ICI-ILD to have better PFS and OS than those with higher-grade ICI-ILD. Among four soluble immune mediators associated with ICI-ILD, a high level of IL-19 was significantly correlated with worse OS and PFS.
CONCLUSION: The identified soluble immune mediators, including CXCL9, MMP-1, IL-6, and IL-19, may be useful as biomarkers to associate with ICI-ILD development. Although we did not detect significant differences in PFS and OS between patients with and without ICI-ILD, PFS and OS were longer in those with lower-grade ICI-ILD than in patients with higher-grade ICI-ILD. Among biomarkers, IL-19 may be a causal and prognostic factor for ICI-ILD.

Keywords:  Chemokine; Cytokine; Immune checkpoint inhibitor; Interstitial lung disease; NSCLC

DOI:  https://doi.org/10.1016/j.lungcan.2023.107351
Curr Radiopharm. 2023 Aug 29.

An Investigation of the Relationship Between 18F-FDG PET/CT Parameters of Primary Tumors and Lymph Node Metastasis in Resectable Non-small Cell Lung Cancer.

Ozan Kandemir, Fadime Demir.

   BACKGROUND: Mediastinal lymph node metastasis is an important prognostic factor in non-small cell lung cancer (NSCLC) patients without distant metastases. 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) is recommended for detecting and staging lymph nodes and distant metastases in NSCLC patients.
OBJECTIVE: This study aims to investigate whether maximum standardized uptake (SUVmax), mean standardized uptake (SUVmean), metabolic tumor volume (MTV), and tumor lesion glycolysis (TLG) values of the primary tumor measured by 18F-FDG PET/CT in resectable NSCLC can predict preoperative lymph node metastasis.
METHODS: This retrospective study included eighty NSCLC patients who underwent preoperative Positron Emission Tomography/Computed Tomography (PET/CT) for diagnosis and staging. The patients were stage I-III and had no distant metastases. Tumor metabolic parameters such as SUVmax, SUVmean, MTV, and TLG at PET/CT imaging were measured for preoperative diagnosis and staging, and the postoperative pathology results of the patients were examined. The pathology results divided patients into two groups; with and without lymph node metastasis. The groups were compared with student's t-test and chi-square test with regard to 18F-FDG PET/CT tumor metabolic parameters and other parameters.
RESULTS: Fifteen (18.8%) patients were female, and 65 (81.3%) were male. According to the postoperative pathology results, while 30 (37.5%) patients had lymph node metastasis, 50 (62.5%) did not. There was a significant difference between the groups regarding tumor SUVmax and SUVmean values (p = 0.036, p = 0.045). Overall survival in the N0 group was significantly higher than in the N1 + N2 group (p = 0.034); median survival was 30.2 months in N0 group cases and 27.3 months in N1 and N2 groups.
CONCLUSION: SUVmax and SUVmean values are significantly higher in patients with lymph node metastases than in patients without lymph node metastases, and this finding may provide useful information for predicting lymph node metastasis in patients with resectable NSCLC.

Keywords:  18F-2-fluoro-2-deoxy-D-glucose; Lymph node metastasis; Maximum standardized uptake value; Mean standardized uptake; Non-small cell lung cancer; Positron emission tomography

DOI:  https://doi.org/10.2174/1874471016666230829100703
Medicine (Baltimore). 2023 Sep 01. 102(35): e34844

Lysosome-related genes: A new prognostic marker for lung adenocarcinoma.

Zeyang Hu, Hang Chen, Hongxiang Li, Shuguang Xu, Yinyu Mu, Qiaoling Pan, Jingtao Tong, Guodong Xu.

Currently, a reliable early prognostic marker has not been identified for lung adenocarcinoma (LUAD), the most common malignancy. Recent studies demonstrated that lysosomal rupture is involved in cancer migration, progression, and immune microenvironment formation. We performed a bioinformatics analysis of lysosomal rupture to investigate whether lysosome-related genes (LRGs) are key in LUAD. The analysis identified 23 LRGs. Cytoscape visualization identified 10 core genes (CCNA2, DLGAP5, BUB1B, KIF2C, PBK, CDC20, NCAPG, ASPM, KIF4A, ANLN). With the 23 LRGs, we established a new risk scoring rule to classify patients with LUAD into high- and low-risk groups and verified the accuracy of the risk score by receiver operating characteristic curves and established a nomogram to evaluate clinical patients. Immunotherapy effectiveness between the high- and low-risk groups was evaluated based on the tumor mutational burden and analyses of immune cell infiltration and drug sensitivity. Pathway enrichment analysis revealed that lysosomes were closely associated with glucose metabolism, amino acid metabolism, and the immune response in patients with LUAD. Lysosomes are a likely new therapeutic target and provide new directions and ideas for treating and managing patients with LUAD.

DOI: https://doi.org/10.1097/MD.0000000000034844
Comput Biol Med. 2023 Aug 29. pii: S0010-4825(23)00880-6. [Epub ahead of print]165 107415

System analysis based on glutamine catabolic-related enzymes identifies GPT2 as a novel immunotherapy target for lung adenocarcinoma.

Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.

   BACKGROUND: In recent years, targeting glutamine metabolism has gained attention as a promising therapeutic approach. Glutamine catabolic-related enzymes play a crucial role in modulating glutamine metabolism and influencing immune responses in the tumor immune microenvironment (TME). However, current literature on the function of glutamine catabolic enzymes in lung adenocarcinoma (LUAD) is limited.
METHODS: We validated the glutamine dependency of LUAD cells in vitro, followed by transcriptome data to identify differentially expressed genes (DEGs), with transcriptome and single-cell data analysis utilized to explore the role of such genes within the tumor immune microenvironment. We performed employed subcutaneous injection of lewis lung carcinoma cells in C57BL/6 mice to confirm the role of candidate genes in tumor growth and anti-tumor immunity.
RESULTS: Our study revealed that glutamine is essential for the growth of LUAD cells. Subsequently, we identified four DEGs - glutamate pyruvate transaminase 1 (GPT1), glutamate pyruvate transaminase 2 (GPT2), glutamic-oxaloacetic transaminase 1 (GOT1), and glutamic-oxaloacetic transaminase 2 (GOT2) - in LUAD patients, which were highly expressed in tumor tissue and associated with an immunosuppressive TME. Single-cell sequencing analysis detected high expression levels of GOT1 and GOT2 in immune and stromal cell subpopulations, while GPT1 and GPT2 showed relatively lower expression. Based on the lower immune score and lower expression in immune and stromal cells, we validated the role of GPT2 in vivo for modulating the TME and tumor growth. Inhibition of GPT2 resulted in suppressed tumor growth and increased the expression of CD4 and CD8. Additionally, GPT2 inhibitors induced a stronger antitumor immunity when used in combination with anti-programmed cell death ligand 1.
CONCLUSION: This study is the first to show the critical role of glutamine catabolic-related enzymes in the TME, and identified GPT2 as a promising therapeutic target for inhibiting tumor growth and improving anti-tumour immune responses for LUAD. Additional studies will be required to define the roles glutamine catabolic-related enzymes play in LUAD.

Keywords:  GPT2; Glutamate pyruvate transaminase 2; Glutamine metabolism; Immunotherapy; Lung adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.compbiomed.2023.107415
J Exp Clin Cancer Res. 2023 Aug 29. 42(1): 221

Exosome nanovesicles as potential biomarkers and immune checkpoint signaling modulators in lung cancer microenvironment: recent advances and emerging concepts.

Naushad Ahmad Khan, Mohammad Asim, Kabir H Biswas, Amani N Alansari, Harman Saman, Mohammad Zahid Sarwar, Kudaibergen Osmonaliev, Shahab Uddin.

  Lung cancer remains the leading cause of cancer-related deaths globally, and the survival rate remains low despite advances in diagnosis and treatment. The progression of lung cancer is a multifaceted and dynamic phenomenon that encompasses interplays among cancerous cells and their microenvironment, which incorporates immune cells. Exosomes, which are small membrane-bound vesicles, are released by numerous cell types in normal and stressful situations to allow communication between cells. Tumor-derived exosomes (TEXs) possess diverse neo-antigens and cargoes such as proteins, RNA, and DNA and have a unique molecular makeup reflecting tumor genetic complexity. TEXs contain both immunosuppressive and immunostimulatory factors and may play a role in immunomodulation by influencing innate and adaptive immune components. Moreover, they transmit signals that contribute to the progression of lung cancer by promoting metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and immunosuppression. This makes them a valuable resource for investigating the immune environment of tumors, which could pave the way for the development of non-invasive biomarkers that could aid in the prognosis, diagnosis, and immunotherapy of lung cancer. While immune checkpoint inhibitor (ICI) immunotherapy has shown promising results in treating initial-stage cancers, most patients eventually develop adaptive resistance over time. Emerging evidence demonstrates that TEXs could serve as a prognostic biomarker for immunotherapeutic response and have a significant impact on both systemic immune suppression and tumor advancement. Therefore, understanding TEXs and their role in lung cancer tumorigenesis and their response to immunotherapies is an exciting research area and needs further investigation. This review highlights the role of TEXs as key contributors to the advancement of lung cancer and their clinical significance in lung immune-oncology, including their possible use as biomarkers for monitoring disease progression and prognosis, as well as emerging shreds of evidence regarding the possibility of using exosomes as targets to improve lung cancer therapy.

Keywords:  Biomarkers; Immune checkpoint signaling inhibitors; Immunotherapy; Lung cancer; Tumor micro-environment; Tumor-derived exosomes

DOI:  https://doi.org/10.1186/s13046-023-02753-7
In Vivo. 2023 Sep-Oct;37(5):37(5): 2357-2364

Smoking Status at Time of Diagnosis Affects the Efficacy of Anti-PD-1/L1 Therapy in Patients With Advanced NSCLC.

Kyu Yean Kim, Jeong Uk Lim, Hye Seon Kang, Ju Sang Kim, Sung Kyoung Kim, Seung Joon Kim, Sang Haak Lee, Chang Dong Yeo.

   BACKGROUND/AIM: Programmed death ligand-1 (PD-L1) expression is known to be a predictive biomarker for response to immunotherapy in non-small cell lung cancer (NSCLC). However, PD-L1 is not always a reliable predictive biomarker. In the present study, we aimed to compare responses to immunotherapy according to smoking status in NSCLC patients receiving immunotherapy in second line or further line treatment.
PATIENTS AND METHODS: The lung cancer registry database of the Catholic Medical Center, Seoul, Republic of Korea was used. Patients were eligible for this study if they were diagnosed with histologically confirmed NSCLC and received immune checkpoint inhibitors (ICIs) as second-line or further line therapy from January 2017 to December 2021.
RESULTS: Overall, 220 patients with NSCLC treated with ICIs were enrolled. There were 40 never smokers, 73 former smokers, and 107 current smokers. In multivariate analysis, smoking status, pathologic type, and PD-L1 expression were significant factors affecting PFS. Sex, ECOG performance status, pathologic type, and PD-L1 expression were significant factors affecting OS.
CONCLUSION: Smoking status at diagnosis of lung cancer could be a predictive biomarker for response to ICIs in patients with advanced NSCLC.

Keywords:  NSCLC; Smoking status; anti-PD-1/L1 therapy

DOI:  https://doi.org/10.21873/invivo.13340
J Immunother Cancer. 2023 Aug;pii: e006770. [Epub ahead of print]11(8):

Location of CD39+ T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer.

Lilian Koppensteiner, Layla Mathieson, Samuel Pattle, David A Dorward, Richard O'Connor, Ahsan R Akram.

   PURPOSE: An improved mechanistic understanding of immunosuppressive pathways in non-small cell lung cancer (NSCLC) is important to develop novel diagnostic and therapeutic approaches. Here, we investigate the prognostic significance of the ectonucleotidases CD39 and CD73 in NSCLC.
EXPERIMENTAL DESIGN: The expression and localization of CD39, CD73 and CD103 was digitally quantified in a cohort of 162 early treatment naïve NSCLC patients using multiplex-immunofluorescence and related to patient outcome. Expression among different cell-populations was assessed via flow cytometry. Targeted RNA-Seq was performed on CD4+ and CD8+ T cells from digested NSCLC tumor tissue and single-cell RNA-Seq data was analyzed to investigate the functional significance of CD39+ T cell populations.
RESULTS: We demonstrate that flow cytometry of early untreated NSCLC patients shows an upregulation of CD39 expression in the tumor tissue among natural killer (NK) cells, fibroblasts and T cells. CD73 expression is mainly found among fibroblasts and Epcam+cells in the tumor tissue. Multiplex Immunofluorescence in a cohort of 162 early untreated NSCLC patients demonstrates that CD39 expression is mainly localized in the tumor stroma while CD73 expression is equally distributed between tumor nest and stroma, and high expression of CD39 and CD73 in the tumor stroma is associated with poor recurrence-free survival (RFS) at 5 years. Additionally, we find that CD8+T cells located in the tumor nest express CD103 and the density of CD39+CD103+CD8+ T cells in the tumor nest predicts improved RFS at 5 years. Targeted RNA-Seq shows that the tumor microenvironment of NSCLC upregulates regulatory pathways in CD4+ T cells and exhaustion in CD8+ T cells, and analysis of a single cell RNA sequencing dataset shows that CD39+CD4+ cells are enriched in Treg signature gene-sets, and CD39+CD103+ cytotoxic T lymphocyte show gene signatures indicative of an exhausted cytotoxic phenotype with upregulated expression of CXCL13.
CONCLUSIONS: Knowledge of patterns of distribution and location are required to understand the prognostic impact of CD39+ T cell populations in NSCLC. This study provides an improved understanding of spatial and functional characteristics of CD39+ T cells and their significance to patient outcome.

Keywords:  biomarkers, tumor; immune checkpoint inhibitors; lung neoplasms; non-small cell lung cancer; tumor biomarkers

DOI:  https://doi.org/10.1136/jitc-2023-006770