bims-meluca 2023-11-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–11–26
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

IL-1β mediates the induction of immune checkpoint regulators IDO1 and PD-L1 in lung adenocarcinoma cells.
Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.
Prognostic significance of body mass index in small-cell lung cancer: Exploring the relationship with skeletal muscle status.
Unravelling the Role of Cancer Cell-Derived Extracellular Vesicles in Muscle Atrophy, Lipolysis, and Cancer-Associated Cachexia.
Radiomics of metastatic brain tumor as a predictive image biomarker of progression-free survival in patients with non-small-cell lung cancer with brain metastasis receiving tyrosine kinase inhibitors.
C-Reactive Protein as an Early Predictor of Efficacy in Advanced Non-Small-Cell Lung Cancer Patients: A Tumor Dynamics-Biomarker Modeling Framework.
Inhibiting LCN2 can suppress the development of NSCLC by promoting ferroptosis.

Cell Commun Signal. 2023 Nov 20. 21(1): 331

IL-1β mediates the induction of immune checkpoint regulators IDO1 and PD-L1 in lung adenocarcinoma cells.

Afshan Fathima Nawas, Ashley Solmonson, Boning Gao, Ralph J DeBerardinis, John D Minna, Maralice Conacci-Sorrell, Carole R Mendelson.

INTRODUCTION: Inflammation plays a significant role in various cancers, including lung cancer, where the inflammatory cytokine IL-1β is often elevated in the tumor microenvironment. Patients with lung adenocarcinoma show higher levels of serum IL-1β compared to healthy individual. Moreover, IL-1β blockade reduces the incidence and mortality of lung cancer. Our prior studies revealed that alveolar type-II cells, the precursors for lung adenocarcinoma, display an induction in the expression of the enzyme tryptophan 2,3-dioxygenase (TDO2) during normal lung development. This induction of TDO2 coincides with an increase in IL-1β levels and is likely caused by IL-1β. Given that cancer cells can co-opt developmentally regulated pathways, we hypothesized that IL-1β may exert its pro-tumoral function by stimulating TDO2 and indoleamine 2, 3-dioxygenase-1 (IDO1), parallel enzymes involved in the conversion of tryptophan (Trp) into the immune-suppressive oncometabolite kynurenine (Kyn). Our goal was to determine whether IL-1β is a common upstream regulator of immune checkpoint regulators.
METHODS: To determine whether IL-1β regulates IDO1, TDO2, PD-L1, and PD-L2, we measured mRNA and protein levels in lung adenocarcinoma cells lines (A549, H1792, H1838, H2347, H2228, HCC364 and HCC827) grown in 2D or 3D and in immortalized normal lung epithelial cells (HBEC3-KT and HSAEC1-KT). To determine the importance of the NFκB pathway in mediating IL-1β -regulated cellular effects, we used siRNA to knockdown RelA/p65 in IL-1β treated cells. The levels of Trp and Kyn in the IL-1β-treated cells and media were measured by mass spectrometry.
RESULTS: Upon IL-1β stimulation, lung adenocarcinoma cells exhibited significant increases in IDO1 mRNA and protein levels, a response that depended on the NFκB pathway. Interestingly, this induction was more pronounced in 3D spheroid cultures compared to monolayer cultures and was not observed in normal immortalized lung epithelial cells. Furthermore, the conversion of Trp to Kyn increased in cells exposed to IL-1β, aligning with the heightened IDO1 expression. Remarkably, IL-1β also upregulated the expression of programmed death ligand-1 (PD-L1) and PD-L2 in multiple cell lines, indicating that IL-1β triggers parallel immune-suppressive mechanisms in lung adenocarcinoma cells.
CONCLUSIONS: Our studies demonstrate that lung adenocarcinoma cells, but not normal immortalized lung epithelial cells, respond to IL-1β signaling by inducing the expression of parallel immune checkpoint proteins that have the potential to promote immune evasion. Video Abstract.

DOI: https://doi.org/10.1186/s12964-023-01348-1
ESMO Open. 2023 Nov 22. pii: S2059-7029(23)01307-8. [Epub ahead of print]8(6): 102066

Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy.

A Abed, A B Beasley, A L Reid, N Law, L Calapre, M Millward, J Lo, E S Gray.

   BACKGROUND: The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual.
MATERIALS AND METHODS: We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy or in combination with chemotherapy. TCR repertoire metrics were correlated with clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression classifier by fitting all four TCR-β repertoire metrics to the immune checkpoint inhibitor (ICI) CBR data. In the subsequent receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities, the best cut-off value was selected to maximise sensitivity to predict CBR to ICI.
RESULTS: We observed an association between reduced number of unique clones and CBR among patients treated with pembrolizumab monotherapy (cohort 1) [risk ratio = 2.86, 95% confidence interval (CI) 1.04-8.73, P = 0.039]. For patients treated with pembrolizumab plus chemotherapy (cohort 2), increased number of unique clones [hazard ratio (HR) = 2.96, 95% CI 1.28-6.88, P = 0.012] and Shannon diversity (HR = 2.73, 95% CI 1.08-6.87, P = 0.033), and reduced evenness (HR = 0.43, 95% CI 0.21-0.90, P = 0.025) and convergence (HR = 0.41, 95% CI 0.19-0.90, P = 0.027) were associated with improved PFS, while only an increased number of unique clones (HR = 4.62, 95% CI 1.52-14.02, P = 0.007) were associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of CBR (cohorts 1 and 2) and were strongly associated with PFS (cohort 1, HR = 0.38, 95% CI 0.19-0.78, P = 0.009) and OS (cohort 2, HR = 0.20, 95% CI 0.05-0.76, P < 0.0001). Reduced TCR conversion was associated with increased frequency of irAEs needing systemic steroid treatment.
CONCLUSION: Combined pre-treatment circulating TCR metrics might serve as a predictive biomarker for clinical outcomes among patients with advanced non-small-cell lung cancer treated with pembrolizumab alone or in combination with chemotherapy.

Keywords:  T-cell receptor repertoire; biomarkers; chemotherapy; immunotherapy; non-small-cell lung cancer

DOI:  https://doi.org/10.1016/j.esmoop.2023.102066
J Cachexia Sarcopenia Muscle. 2023 Nov 20.

Prognostic significance of body mass index in small-cell lung cancer: Exploring the relationship with skeletal muscle status.

Yong Jae Kwon, Young Cheol Yoon, Hyun Su Kim, Min Jae Cha, Sehhoon Park, Ji Hyun Lee.

   BACKGROUND: We investigated the prognostic significance of body mass index in small-cell lung cancer and explored whether skeletal muscle status affects the body mass index-survival relationship.
METHODS: This retrospective study evaluated data from patients who underwent platinum-etoposide chemotherapy for small-cell lung cancer between March 2010 and December 2021. Skeletal muscle status was assessed using non-contrast computed tomography images of baseline positron-emission tomography-computed tomography, with the skeletal muscle index defined as the cross-sectional area of skeletal muscle divided by height squared, and the average attenuation values of skeletal muscle. Cox proportional hazards regression analysis was used to determine the correlations of body mass index, skeletal muscle metrics, and overall survival.
RESULTS: We analysed the data of 1146 Asian patients (1006 men and 140 women, with a median age of 67 years [interquartile range: 61-72 years]), including 507 and 639 patients with limited and extensive disease, respectively. Being underweight, defined as a body mass index <18.5 kg/m2 , was associated with shorter overall survival, independent of clinical covariates in both the limited-disease (hazard ratio, 1.77; 95% confidence interval, 1.01-3.09) and extensive-disease (hazard ratio, 1.71; 95% confidence interval, 1.18-2.48) groups. The prognostic value of being underweight remained significant after additional adjustment for skeletal muscle index and attenuation in both limited-disease (hazard ratio, 1.96; 95% confidence interval, 1.09-3.51) and extensive-disease (hazard ratio, 1.75; 95% confidence interval, 1.17-2.61) groups.
CONCLUSIONS: Being underweight is an independent poor prognostic factor for shorter overall survival in Asian patients with small-cell lung cancer, regardless of skeletal muscle status.

Keywords:  Body mass index; Myopenia; Myosteatosis; Prognosis; Sarcopenia; Skeletal muscle; Small-cell lung cancer

DOI:  https://doi.org/10.1002/jcsm.13345
Cells. 2023 Nov 09. pii: 2598. [Epub ahead of print]12(22):

Unravelling the Role of Cancer Cell-Derived Extracellular Vesicles in Muscle Atrophy, Lipolysis, and Cancer-Associated Cachexia.

Akbar L Marzan, Sai V Chitti.

  Cancer-associated cachexia is a metabolic syndrome that causes significant reduction in whole-body weight due to excessive loss of muscle mass accompanied by loss of fat mass. Reduced food intake and several metabolic abnormalities, such as increased energy expenditure, excessive catabolism, and inflammation, are known to drive cachexia. It is well documented that cancer cells secrete EVs in abundance which can be easily taken up by the recipient cell. The cargo biomolecules carried by the EVs have the potential to alter the signalling pathways and function of the recipient cells. EV cargo includes proteins, nucleic acids, lipids, and metabolites. Tumour-secreted EVs have been found to alter the metabolic and biological functions of adipose and muscle tissue, which aids in the development of the cachexia phenotype. To date, no medical intervention or FDA-approved drug exists that can completely reverse cachexia. Therefore, understanding how cancer-derived EVs contribute to the onset and progression of cancer-associated cachexia may help with the identification of new biomarkers as well as provide access to novel treatment alternatives. The goal of this review article is to discuss the most recent research on cancer-derived EVs and their function in cellular crosstalk that promotes catabolism in muscle and adipose tissue during cancer-induced cachexia.

Keywords:  browning; cancer-associated cachexia; extracellular vesicles; lipolysis; muscle atrophy

DOI:  https://doi.org/10.3390/cells12222598
Transl Oncol. 2023 Nov 18. pii: S1936-5233(23)00212-7. [Epub ahead of print]39 101826

Radiomics of metastatic brain tumor as a predictive image biomarker of progression-free survival in patients with non-small-cell lung cancer with brain metastasis receiving tyrosine kinase inhibitors.

Ting-Wei Wang, Heng-Sheng Chao, Hwa-Yen Chiu, Chia-Feng Lu, Chien-Yi Liao, Yen Lee, Jyun-Ru Chen, Tsu-Hui Shiao, Yuh-Min Chen, Yu-Te Wu.

   BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) are the first-line therapy for EGFR-mutant non-small-cell lung cancer (NSCLC). Early prediction of treatment failure in patients with brain metastases treated with EGFR-TKIs may help in making decisions for systemic drug therapy or local brain tumor control. This study examined the predictive power of the radiomics of both brain metastasis tumors and primary lung tumors. We propose a deep learning based CoxCC model based on quantitative brain magnetic resonance imaging (MRI), a prognostic index and clinical data; the model can be used to predict progression-free survival (PFS) after EGFR-TKI therapy in advanced EGFR-mutant NSCLC.
METHODS: This retrospective single-center study included 271 patients receiving first-line EGFR-TKI targeted therapy in 2018-2019. Among them, 72 patients who had brain metastases before receiving first-line EGFR-TKI treatment. Three radiomic features were extracted from pretreatment brain MRI images. A CoxCC model for the progression risk stratification of EGFR-TKI treatment was proposed on the basis of MRI radiomics, clinical features, and a prognostic index. We performed time-dependent PFS predictions to evaluate the performance of the CoxCC model.
RESULTS: The CoxCC model based on a prognostic index, clinical features, and radiomic features of brain metastasis exhibited higher performance than clinical features combined with indexes previously proposed for determining the prognosis of brain metastasis, including recursive partitioning analysis, diagnostic-specific graded prognostic assessment, graded prognostic assessment for lung cancer using molecular markers (lung-molGPA), and modified lung-molGPA, with c-index values of 0.75, 0.67, 0.66, 0.65, and 0.65, respectively. The model achieved areas under the curve of 0.88, 0.73, 0.92, and 0.90 for predicting PFS at 3, 6, 9 and 12 months, respectively. PFS significantly differed between the high- and low-risk groups (p < 0.001).
CONCLUSIONS: For patients with advanced-stage NSCLC with brain metastasis, MRI radiomics of brain metastases may predict PFS. The CoxCC model integrating brain metastasis radiomics, clinical features, and a prognostic index provided reliable multi-time-point PFS predictions for patients with advanced NSCLC and brain metastases receiving EGFR-TKI treatment.

Keywords:  Deep learning; Epidermal growth factor receptor–tyrosine kinase inhibitors; Non-small-cell lung cancer with brain metastasis; Radiomics; Treatment outcome prediction

DOI:  https://doi.org/10.1016/j.tranon.2023.101826
Cancers (Basel). 2023 Nov 15. pii: 5429. [Epub ahead of print]15(22):

C-Reactive Protein as an Early Predictor of Efficacy in Advanced Non-Small-Cell Lung Cancer Patients: A Tumor Dynamics-Biomarker Modeling Framework.

Yomna M Nassar, Francis Williams Ojara, Alejandro Pérez-Pitarch, Kimberly Geiger, Wilhelm Huisinga, Niklas Hartung, Robin Michelet, Stefan Holdenrieder, Markus Joerger, Charlotte Kloft.

  In oncology, longitudinal biomarkers reflecting the patient's status and disease evolution can offer reliable predictions of the patient's response to treatment and prognosis. By leveraging clinical data in patients with advanced non-small-cell lung cancer receiving first-line chemotherapy, we aimed to develop a framework combining anticancer drug exposure, tumor dynamics (RECIST criteria), and C-reactive protein (CRP) concentrations, using nonlinear mixed-effects models, to evaluate and quantify by means of parametric time-to-event models the significance of early longitudinal predictors of progression-free survival (PFS) and overall survival (OS). Tumor dynamics was characterized by a tumor size (TS) model accounting for anticancer drug exposure and development of drug resistance. CRP concentrations over time were characterized by a turnover model. An x-fold change in TS from baseline linearly affected CRP production. CRP concentration at treatment cycle 3 (day 42) and the difference between CRP concentration at treatment cycles 3 and 2 were the strongest predictors of PFS and OS. Measuring longitudinal CRP allows for the monitoring of inflammatory levels and, along with its reduction across treatment cycles, presents a promising prognostic marker. This framework could be applied to other treatment modalities such as immunotherapies or targeted therapies allowing the timely identification of patients at risk of early progression and/or short survival to spare them unnecessary toxicities and provide alternative treatment decisions.

Keywords:  C-reactive protein; biomarkers; non-small-cell lung cancer; nonlinear mixed-effects modeling; overall survival; prognosis; progression-free survival; time-to-event analysis

DOI:  https://doi.org/10.3390/cancers15225429
Gene. 2023 Nov 22. pii: S0378-1119(23)00867-3. [Epub ahead of print] 148026

Inhibiting LCN2 can suppress the development of NSCLC by promoting ferroptosis.

Zhongjun Pan, Ben Li, Peng Lu, Guoxiang Rong, Xiaowei Wang.

   BACKGROUND: Tumor progression is intricately linked to ferroptosis, a recently discovered form of regulated cell death. However, the specific causes of ferroptosis in non-small cell lung cancer (NSCLC) remain unclear.
METHODS: In this study, we conducted transcriptome sequencing on NSCLC samples and identified Lipocalin-2 (LCN2) as a significantly differentially expressed gene associated with ferroptosis in NSCLC. Through the intersection of the set of significantly different genes with ferroptosis-related genes, we unveiled the relevance of LCN2 in NSCLC. To validate our findings, several cell lines (BEAS-2B, A549, H1299, PC-9, H1975) were utilized, and Western blot (WB) analysis was performed. We employed a variety of assays, including CCK8, EDU, scratch, Transwell, and specific assays targeting ferroptosis, to investigate the effects of LCN2 on NSCLC cell proliferation, migration, and ferroptosis. Additionally, LCN2 was evaluated in vivo using a mouse tumor xenograft model.
RESULTS: In both NSCLC patients and cells, LCN2 exhibited upregulation and was associated with a poor prognosis. Inhibition of LCN2 promoted ferroptosis, resulting in the inhibition of NSCLC proliferation and migration. Conversely, the ferroptosis inhibitor Fer-1 promoted NSCLC cell proliferation and migration while inhibiting ferroptosis. Furthermore, down-regulating LCN2 reduced Fer-1's promotion of NSCLC cell migration and proliferation, as well as its prevention of ferroptosis. In vivo inhibition of LCN2 prevented NSCLC cell growth and enhanced ferroptosis.
CONCLUSION: Based on our research, reducing LCN2 could effectively induce ferroptosis and hinder the growth of NSCLC.

Keywords:  Ferroptosis; LCN2; Migration; NSCLC; Proliferation

DOI:  https://doi.org/10.1016/j.gene.2023.148026