bims-meluca 2022-12-25 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–12–25
twenty-one papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Significance of preoperative evaluation of skeletal muscle index and immune-nutritional status for patients with early-stage non-small cell lung cancer.
Targeting EGFR in Combination with Nutritional Supplements on Antitumor Efficacy in a Lung Cancer Mouse Model.
Inhibition of TIGAR Increases Exogenous p53 and Cisplatin Combination Sensitivity in Lung Cancer Cells by Regulating Glycolytic Flux.
Establishing a whole blood CD4+ T cell immunity measurement to predict response to anti-PD-1.
Characterization of the fatty acid metabolism-related genes in lung adenocarcinoma to guide clinical therapy.
Plasma tumor mutation burden is associated with clinical benefit in patients with non-small cell lung cancer treated with anti-programmed death-1 monotherapy.
Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC.
Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1.
Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer.
Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.
Predictive Value of Baseline FDG-PET/CT for the Durable Response to Immune Checkpoint Inhibition in NSCLC Patients Using the Morphological and Metabolic Features of Primary Tumors.
Identification of prognostic factors and nomogram model for patients with advanced lung cancer receiving immune checkpoint inhibitors.
Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.
Potential Role of Tumor-Derived Exosomes in Non-Small-Cell Lung Cancer in the Era of Immunotherapy.
A tumor-associated autoantibody panel for the detection of non-small cell lung cancer.
Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-cancer activity in MYC-overexpressing high-grade serous ovarian carcinoma.
HNRNPC, a predictor of prognosis and immunotherapy response based on bioinformatics analysis, is related to proliferation and invasion of NSCLC cells.
Identification of an Amino Acid Metabolism-Related Gene Signature for Predicting Prognosis in Lung Adenocarcinoma.
Metabolic reprogramming of glutamine involved in tumorigenesis, multidrug resistance and tumor immunity.
Tumor immune microenvironment and immunotherapy efficacy in BRAF mutation non-small-cell lung cancer.
Prognostic value of RILPL2 and its correlation with tumor immune microenvironment and glycolysis in non-small cell lung cancer.

Gen Thorac Cardiovasc Surg. 2022 Dec 23.

Significance of preoperative evaluation of skeletal muscle index and immune-nutritional status for patients with early-stage non-small cell lung cancer.

Seijiro Sato, Mao Sato, Hirohiko Shinohara.

   OBJECTIVES: Sarcopenia involves several mechanisms, including age-related changes, nutritional deficiencies, and inflammation, and is associated with unfavorable clinical outcomes. However, the significance of skeletal muscle index (SMI) and immune-nutritional status for patients with early-stage non-small cell lung cancer (NSCLC) remains unclear. This retrospective study was performed to investigate associations between preoperative SMI based on computed tomography (CT) at the L1 level and immune-nutritional status, and whether these factors correlated with surgical outcomes.
METHODS: We retrospectively investigated 386 patients with stage I-II NSCLC who underwent curative anatomical pulmonary resection. SMI was assessed on CT at the L1 level and patients were divided into low-SMI (n = 97) and high-SMI (n = 289) groups. We examined the significance of SMI for postoperative outcomes and evaluated correlations between SMI and clinical characteristics, including immune-nutritional status.
RESULTS: Low SMI was significantly associated with body mass index and geriatric nutritional risk index. Five-year overall survival rate was significantly lower in the low-SMI group (66.0%) than in the high-SMI group (82.2%, P = 0.004). Multivariate analysis revealed SMI (hazard ratio [HR] 1.850; 95% confidence interval [CI] 1.091-3.135; P = 0.022) and prognostic nutritional index (PNI) (HR 2.031; 95% CI 1.231-3.352; P = 0.006) as independent predictors of overall survival. Low SMI correlated significantly with postoperative complications (P = 0.024).
CONCLUSIONS: Low preoperative SMI based on CT at the L1 level appears associated with poor prognosis and postoperative complications among patients with early-stage NSCLC. PNI is also an independent prognostic factor for surgical outcomes.

Keywords:  Anatomical pulmonary resection; Lung cancer; Prognostic nutritional index; Sarcopenia; Skeletal muscle index

DOI:  https://doi.org/10.1007/s11748-022-01899-z
Mar Drugs. 2022 Nov 29. pii: 751. [Epub ahead of print]20(12):

Targeting EGFR in Combination with Nutritional Supplements on Antitumor Efficacy in a Lung Cancer Mouse Model.

Chih-Hung Guo, Wen-Chin Li, Chia-Lin Peng, Pei-Chung Chen, Shih-Yu Lee, Simon Hsia.

  Selenium (Se) and fish oil (FO) exert anti-epidermal growth factor receptor (EGFR) action on tumors. This study aimed to compare the anti-cancer efficacy of EGFR inhibitors (gefitinib and erlotinib) alone and in combination with nutritional supplements of Se/FO in treating lung cancer. Lewis LLC1 tumor-bearing mice were treated with a vehicle or Se/FO, gefitinib or gefitinib plus Se/FO, and erlotinib or erlotinib plus Se/FO. The tumors were assessed for mRNA and protein expressions of relevant signaling molecules. Untreated tumor-bearing mice had the lowest body weight and highest tumor weight and volume of all the mice. Mice receiving the combination treatment with Se/FO and gefitinib or erlotinib had a lower tumor volume and weight and fewer metastases than did those treated with gefitinib or erlotinib alone. The combination treatment exhibited greater alterations in receptor signaling molecules (lower EGFR/TGF-β/TβR/AXL/Wnt3a/Wnt5a/FZD7/β-catenin; higher GSK-3β) and immune checkpoint molecules (lower PD-1/PD-L1/CD80/CTLA-4/IL-6; higher NKp46/CD16/CD28/IL-2). These mouse tumors also had lower angiogenesis, cancer stemness, epithelial to mesenchymal transitions, metastases, and proliferation of Ki-67, as well as higher cell cycle arrest and apoptosis. These preliminary results showed the Se/FO treatment enhanced the therapeutic efficacies of gefitinib and erlotinib via modulating multiple signaling pathways in an LLC1-bearing mouse model.

Keywords:  Lewis lung carcinoma; anti-tumor signaling pathway; erlotinib; fish oil; gefitinib; mice; selenium

DOI:  https://doi.org/10.3390/md20120751
Int J Mol Sci. 2022 Dec 16. pii: 16034. [Epub ahead of print]23(24):

Inhibition of TIGAR Increases Exogenous p53 and Cisplatin Combination Sensitivity in Lung Cancer Cells by Regulating Glycolytic Flux.

Jiaying Fu, Sihang Yu, Xiyao Zhao, Chaoke Zhang, Luyan Shen, Yanan Liu, Huimei Yu.

  The metabolism and apoptosis of tumor cells are important factors that increase their sensitivity to chemotherapeutic drugs. p53 and cisplatin not only induce tumor cell apoptosis, but also regulate the tumor cell metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) can inhibit glycolysis and promote more glucose metabolism in the pentose phosphate pathway. We speculate that the regulation of the TIGAR by the combination therapy of p53 and cisplatin plays an important role in increasing the sensitivity of tumor cells to cisplatin. In this study, we found that the combined treatment of p53 and cisplatin was able to inhibit the mitochondrial function, promote mitochondrial pathway-induced apoptosis, and increase the sensitivity. Furthermore, the expression of the TIGAR was inhibited after a combined p53 and cisplatin treatment, the features of the TIGAR that regulate the pentose phosphate pathway were inhibited, the glucose flux shifted towards glycolysis, and the localization of the complex of the TIGAR and Hexokinase 2 (HK2) on the mitochondria was also reduced. Therefore, the combined treatment of p53 and cisplatin may modulate a glycolytic flux through the TIGAR, altering the cellular metabolic patterns while increasing apoptosis. Taken together, our findings reveal that the TIGAR may serve as a potential therapeutic target to increase the sensitivity of lung cancer A549 cells to cisplatin.

Keywords:  A549 cells; TIGAR; apoptosis; cisplatin; p53

DOI:  https://doi.org/10.3390/ijms232416034
BMC Cancer. 2022 Dec 17. 22(1): 1325

Establishing a whole blood CD4+ T cell immunity measurement to predict response to anti-PD-1.

Ou Yamaguchi, Kazuyuki Atarashi, Kenichi Yoshimura, Ayako Shiono, Atsuhito Mouri, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Yoshiaki Miyamoto, Hitoshi Uga, Nobuo Seki, Tomoko Matsushima, Norihiro Kikukawa, Kunihiko Kobayashi, Kyoichi Kaira, Hiroshi Kagamu.

   BACKGROUND: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index.
METHODS: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer.
RESULTS: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments.
CONCLUSIONS: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

Keywords:  Biomarkers; Effector CD4+ T cells; Flow cytometry; Non-small cell lung cancer; PD-1 blockade therapy

DOI:  https://doi.org/10.1186/s12885-022-10445-2
BMC Pulm Med. 2022 Dec 23. 22(1): 486

Characterization of the fatty acid metabolism-related genes in lung adenocarcinoma to guide clinical therapy.

Guichuan Huang, Jing Zhang, Ling Gong, Xiaowen Wang, Bangyan Zhang, Daishun Liu.

   BACKGROUND: Lung adenocarcinoma (LUAD) is a common cancer with a bad prognosis. Numerous investigations have indicated that the metabolism of fatty acids plays an important role in the occurrence, progression, and treatment of cancer. Consequently, the objective of the current investigation was to elucidate the role and prognostic significance of genes associated with fatty acid metabolism in patients diagnosed with LUAD.
MATERIALS AND METHODS: The data files were acquired from The Cancer Genome Atlas database and GSE31210 dataset. Univariate Cox and least absolute shrinkage and selection operator regression analyses were conducted to establish a prognostic risk scoring model depending on fatty acid metabolism-associated genes to predict the prognosis of patients with LUAD. pRRophetic algorithm was utilized to evaluate the potential therapeutic agents. Gene set variation analysis combined with cell-type identification based on the estimation of relative subsets of RNA transcript and single-sample gene set enrichment analysis was used to determine the association between immune cell infiltration and risk score. Tumor immune dysfunction and exclusion algorithm was employed to predict immunotherapeutic sensitivity.
RESULTS: To forecast the prognosis of patients with LUAD, a risk scoring model based on five genes associated with fatty acid metabolism was developed, including LDHA, ALDOA, CYP4B1, DPEP2, and HPGDS. Using the risk score algorithm, patients were divided into higher- and lower-risk categories. Patients classified as minimal risk showed superior prognosis than those with elevated risk. In addition, individuals in the higher-risk group had a proclivity toward chemoresistance and amenable to immunotherapy.
CONCLUSION: The prognostic risk scoring model aids in estimating the prognosis of LUAD patients. It may also provide new insights into LUAD carcinogenesis and therapeutic strategies.

Keywords:  Fatty acid metabolism; Lung adenocarcinoma; Prognosis; Risk score model

DOI:  https://doi.org/10.1186/s12890-022-02286-3
Ther Adv Med Oncol. 2022 ;14 17588359221141761

Plasma tumor mutation burden is associated with clinical benefit in patients with non-small cell lung cancer treated with anti-programmed death-1 monotherapy.

Jii Bum Lee, Hyung Soon Park, Su Jin Choi, Seong Gu Heo, Ho Jung An, Hye Ryun Kim, Min Hee Hong, Sun Min Lim, Kyle Chang, Katie Quinn, Justin Odegaard, Byoung Yong Shim, Byoung Chul Cho.

   Background: The clinical utility of plasma tumor mutational burden (pTMB) requires further validation. Herein, the pTMB and genetic alterations were investigated as predictive biomarkers for anti-PD-1 monotherapy outcome in metastatic non-small cell lung cancer (NSCLC).
Methods: The GuardantOMNI panel (Guardant Health) was used to identify pTMB and genetic alterations. Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Associations between pTMB and clinical benefit rate (CBR, stable disease ⩾6 months or partial response), progression-free survival (PFS), and overall survival (OS) were assessed.
Results: Median pTMB in 84 patients was 10.8 mutations/megabase (mut/Mb). Histological analyses revealed that 61 and 36% of the patients had adenocarcinomas and squamous NSCLC, respectively. Most patients were treated with nivolumab (74%) and most anti-PD-1 agents were administered as second-line treatment (70%). The median follow-up duration was of 10.9 months (range, 0.2-40.7). Patients with high pTMB (⩾19 mut/Mb) had a higher CBR (69%) compared with low pTMB patients (33%; p = 0.01). ARID1A (p = 0.007) and either ERBB2 or KIT mutations (p = 0.012) were positive and negative determinants, respectively, for clinical benefit. Multivariate analysis further showed that high pTMB was an independent predictive biomarker for both PFS [hazard ratio (HR) = 0.44, 95% confidence interval (CI): 0.22-0.88, p = 0.02] and OS (HR = 0.37, 95% CI: 0.18-0.76, p = 0.007).
Conclusion: High pTMB (⩾19 mut/Mb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents.

Keywords:  anti-PD-1; clinical benefit; genetic alterations; non-small cell lung cancer; plasma tumor mutational burden

DOI:  https://doi.org/10.1177/17588359221141761
Life (Basel). 2022 Dec 13. pii: 2092. [Epub ahead of print]12(12):

Baseline Ang-2 Serum Levels as a Predictive Factor for Survival in NSCLC and SCLC.

Asimina Nikolakopoulou, Dimitris Tsakogiannis, Flora Zagouri, Eleni Zografos, Lamprini Tzioga, Grigorios Stratakos, Nikolaos Koulouris, Konstantinos Syrigos, Garyfalia Bletsa.

  Angiopoietin-2 (Ang-2) has been implicated in the development of several types of cancer, including lung malignancy. In the present study, we examined the impact of Ang-2 serum concentration on the development, dissemination, and 5-year overall survival of NSCLC and SCLC. A total of 99 patients with lung cancer were tested. The OS of NSCLC and SCLC patients was estimated using Kaplan-Meier curves and compared through log-rank test. The median serum level of Ang-2 at baseline in both NSCLC and SCLC patients was significantly higher than that of controls (p < 0.0001). The Ang-2 serum concentration was not related to metastasis, neither in NSCLC nor in SCLC cases. The OS was found to be significantly shorter for stage IIIβ NSCLC patients with a high baseline Ang-2 serum concentration (p = 0.012), while Cox regression analysis showed that Ang-2 is a significant independent factor for poor prognosis for stage IIIβ NSCLC (hazard ratio = 2.97, 95% CI: 1.05-8.40, p = 0.04). The concentration of Ang-2 has no impact on the prognosis of SCLC. Ang-2 could be considered as a significant molecular marker that enables the prediction of NSCLC and SCLC development, and is involved in the poor prognosis of stage IIIβ NSCLC.

Keywords:  Ang-2; NSCLC; SCLC; angiopoietins; lung cancer; prognostic factor

DOI:  https://doi.org/10.3390/life12122092
J Oncol. 2022 ;2022 3425841

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1.

Ruishuang Ma, Xin Li, Shengping Gong, Xiaoqin Ge, Ting Zhu, Xiaoxu Ge, Lijuan Weng, Qingsong Tao, Jianxin Guo.

Lactate is critical in modeling tumor microenvironment causing chemotherapy resistance; however, the role of lactate in tyrosine kinase inhibitor (TKI) resistance has not been fully known. The aim of this study was to evaluate whether lactate could mediate TKI resistance through GPR81 and MCT1 in non-small-cell lung cancer (NSCLC). Here, we showed that lactate enhanced the cell viability and restrained erlotinib-induced apoptosis in PC9 and HCC827 cells. GPR81 and AKT expression were significantly increased with the addition of lactate, and siGPR81 reduced AKT expression resulting in a raised apoptosis rate with erlotinib treatment. Furthermore, we found that lactate also promoted MCT1 exposure, and inhibiting MCT1 with AZD3965 markedly impaired the glycolytic capacity. A significant increase of GPR81 and MCT1 expression was observed in insensitive tissues compared with sensitive ones by immunostaining in NSCLC patients. Our results indicate that lactate adopts dual strategies to promote TKI resistance in NSCLC, not only activating AKT signaling by GPR81, but also giving energy supply through MCT1-mediated input. Targeting GPR81 and MCT1 may provide new therapeutic modalities for TKI resistance in NSCLC.

DOI: https://doi.org/10.1155/2022/3425841
Front Immunol. 2022 ;13 1058531

Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer.

Audrey Brisebarre, Julien Ancel, Théophile Ponchel, Emma Loeffler, Adeline Germain, Véronique Dalstein, Valérian Dormoy, Anne Durlach, Gonzague Delepine, Gaëtan Deslée, Myriam Polette, Béatrice Nawrocki-Raby.

   Introduction: In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHITlow/pHER2high phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance.
Materials and methods: We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHITlow/pHER2high signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI).
Results: We showed that up-regulated genes in FHITlow/pHER2high tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHITlow/pHER2high signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHITlow/pHER2high tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts.
Conclusion: These data suggest that ICI might not be a relevant option for NSCLC patients with FHITlow/pHER2high tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.

Keywords:  FHIT; HER2; NSCLC; immunotherapy response; prognosis; transcriptomic signature

DOI:  https://doi.org/10.3389/fimmu.2022.1058531
FEBS J. 2022 Dec 19.

Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.

Min Zhang, Xiaoyu Duan, Lu Wang, Jing Wen, Pingfei Fang.

  Mild hypothermia can induce apoptotic cell death in many cancer cells, but the underlying mechanisms remain unclear. In a genetic screen in C. elegans, we found that impaired endoplasmic reticulum unfolded protein response (UPRER ) increased animal survival after cold shock. Consistently, in normal human lung cells, decreasing culture temperature from 37°C to 30°C activated UPRER and promoted cell death. However, lung adenocarcinoma cells were impaired in UPRER induction and resistant to hypothermia-induced cell death. Mechanistically, hypothermic stress increased HSF1 levels, which in turn activated UPRER to promote apoptotic cell death. HSF1 expression was associated with UPRER genes in normal tissues but such association was lost in many cancers, especially lung adenocarcinoma. Activating UPRER enhanced the cytotoxicity of chemotherapy drugs cisplatin preferentially in cancer cells. Consistently, cancer patients with higher UPRER expression had generally better prognosis. Together, our study on hypothermia has led to the discovery of HSF1-UPRER in the regulation of drug sensitivity in lung cancer cells, providing novel thoughts on developing new strategies against chemoresistance.

Keywords:  HSF1; chemoresistance; hypothermia; lung cancer; unfolded protein response

DOI:  https://doi.org/10.1111/febs.16709
Cancers (Basel). 2022 Dec 11. pii: 6095. [Epub ahead of print]14(24):

Predictive Value of Baseline FDG-PET/CT for the Durable Response to Immune Checkpoint Inhibition in NSCLC Patients Using the Morphological and Metabolic Features of Primary Tumors.

Ken Kudura, Nando Ritz, Tim Kutzker, Martin H K Hoffmann, Arnoud J Templeton, Robert Foerster, Michael C Kreissl, Kwadwo Antwi.

   OBJECTIVES: We aimed to investigate the predictive value of baseline 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) for durable responses to immune checkpoint inhibitors (ICIs) by linking the morphological and metabolic features of primary tumors (PTs) in nonsmall cell lung cancer (NSCLC) patients.
METHODS: For the purpose of this single-center study, the imaging data of the patients with a first diagnosis of NSCLC and an available baseline FDG-PET/CT between 2020 and 2021 were retrospectively assessed. The baseline characteristics were collected based on clinical reports and interdisciplinary tumor board documentation. The metabolic (such as standardized uptake value SUV maximum and mean (SUVmax, SUV mean), metabolic tumor volume (MTV), total lesion glycolysis (TLG)) and morphological (such as volume, morphology, margin, and presence of lymphangiosis through imaging) features of all the PTs were retrospectively assessed using FDG-PET/CT. Overall survival (OS), progression-free survival (PFS), clinical benefit (CB) and mortality rate were used as endpoints to define the long-term response to therapy. A backward, stepwise logistic regression analysis was performed in order to define the best model for predicting lasting responses to treatment. Statistical significance was assumed at p < 0.05.
RESULTS: A total of 125 patients (median age ± standard deviation (SD) 72.0 ± 9.5 years) were enrolled: 64 men (51.2%) and 61 women (48.8%). Adenocarcinoma was by far the most common histological subtype of NSCLC (47.2%). At the initial diagnosis, the vast majority of all the included patients showed either locally advanced disease (34.4%) or metastatic disease (36.8%). Fifty patients were treated with ICIs either as a first-line (20%) or second-line (20%) therapy, while 75 patients did not receive ICIs. The median values ± SD of PT SUVmax, mean, MTV, and TLG were respectively 10.1 ± 6.0, 6.1 ± 3.5, 13.5 ± 30.7, and 71.4 ± 247.7. The median volume of PT ± SD was 13.7 ± 30.7 cm3. The PTs were most frequently solid (86.4%) with irregular margins (76.8%). Furthermore, in one out of five cases, the morphological evidence of lymphangiosis was seen through imaging (n = 25). The median follow-up ± SD was 18.93 ± 6.98 months. The median values ± SD of OS and PFS were, respectively, 14.80 ± 8.68 months and 14.03 ± 9.02 months. Age, PT volume, SUVmax, TLG, the presence of lymphangiosis features through imaging, and clinical stage IV were very strong long-term outcome predictors of patients treated with ICIs, while no significant outcome predictors could be found for the cohort with no ICI treatment. The optimal cut-off values were determined for PT volume (26.94 cm3) and SUVmax (15.05). Finally, 58% of NSCLC patients treated with ICIs had a CB vs. 78.7% of patients in the cohort with no ICI treatment. However, almost all patients treated with ICIs and with disease progression over time died (mortality in the case of disease progression 95% vs. 62.5% in the cohort without ICIs). Conclusion: Baseline FDG-PET/CT could be used to predict a durable response to ICIs in NSCLC patients. Age, clinical stage IV, lymphangiosis features through imaging, PT volume (thus PT MTV due to a previously demonstrated linear correlation), PT SUVmax, and TLG were very strong long-term outcome predictors. Our results highlight the importance of linking clinical data, as much as morphological features, to the metabolic parameters of primary tumors in a multivariate outcome-predicting model using baseline FDG-PET/CT.

Keywords:  CTLA-4; NSCLC; PD-1; PD-L1; immunotherapy; lung cancer; outcome prediction; positron emission tomography computed tomography

DOI:  https://doi.org/10.3390/cancers14246095
PeerJ. 2022 ;10 e14566

Identification of prognostic factors and nomogram model for patients with advanced lung cancer receiving immune checkpoint inhibitors.

Xiuqiong Chen, Zhaona Li, Jing Zhou, Qianhui Wei, Xinyue Wang, Richeng Jiang.

   Background and aim: Some patients with lung cancer can benefit from immunotherapy, but the biomarkers that predict immunotherapy response were not well defined. Baseline characteristic of patients may be the most convenient and effective markers. Therefore, our study was designed to explore the association between baseline characteristics of patients with lung cancer and the efficacy of immunotherapy.
Methods: A total of 216 lung cancer patients from Tianjin Medical University Cancer Institute & Hospital who received immunotherapy between 2017 and 2021 were included in the retrospective analysis. All baseline characteristic data were collected and then univariate log-rank analysis and multivariate COX regression analysis were performed. Kaplan-Meier analysis was used to evaluate patients' progression-free survival (PFS). A nomogram based on significant biomarkers was constructed to predict PFS rate of patients receiving immunotherapy. We evaluated the prediction accuracy of nomogram using C-indices and calibration curves.
Results: Univariate analysis of all collected baseline factors showed that age, clinical stage, white blood cell (WBC), lymphocyte (LYM), monocyte (MON), eosinophils (AEC), hemoglobin (HB), lactate dehydrogenase (LDH), albumin (ALB) and treatment line were significantly associated with PFS after immunotherapy. Then these 10 risk factors were included in a multivariate regression analysis, which indicated that age (HR: 1.95, 95% CI [1.01-3.78], P = 0.048), MON (HR: 1.74, 95% CI [1.07-2.81], P = 0.025), LDH (HR: 0.59, 95% CI [0.36-0.95], P = 0.030), and line (HR: 0.57, 95% CI [0.35-0.94], P = 0.026) were significantly associated with PFS in patients with lung cancer receiving immunotherapy. Patients with higher ALB showed a greater trend of benefit compared with patients with lower ALB (HR: 1.58, 95% CI [0.94-2.66], P = 0.084). Patients aged ≥51 years, with high ALB, low LDH, first-line immunotherapy, and high MON had better response rates and clinical benefits. The nomogram based on age, ALB, MON, LDH, line was established to predict the prognosis of patients treated with immune checkpoint inhibitor (ICI). The C-index of training cohort and validation cohort were close, 0.71 and 0.75, respectively. The fitting degree of calibration curve was high, which confirmed the high prediction value of our nomogram.
Conclusion: Age, ALB, MON, LDH, line can be used as reliable predictive biomarkers for PFS, response rate and cancer control in patients with lung cancer receiving immunotherapy. The nomogram based on age, ALB, MON, LDH, line was of great significance for predicting 1-year-PFS, 2-year-PFS and 3-year-PFS in patients with advanced lung cancer treated with immunotherapy.

Keywords:  Biomarkers; Immunotherapy; Lung cancer; Nomogram; Progression-free survival

DOI:  https://doi.org/10.7717/peerj.14566
Genes (Basel). 2022 Nov 22. pii: 2183. [Epub ahead of print]13(12):

Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.

Shigetoshi Nishihara, Toshimitsu Yamaoka, Fumihiro Ishikawa, Kensuke Higuchi, Yuki Hasebe, Ryo Manabe, Yasunari Kishino, Sojiro Kusumoto, Koichi Ando, Yusuke Kuroda, Tohru Ohmori, Hironori Sagara, Hitoshi Yoshida, Junji Tsurutani.

  Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

Keywords:  EGFR-TKI; EGFR-mutated NSCLC; apoptosis; combination therapies

DOI:  https://doi.org/10.3390/genes13122183
Life (Basel). 2022 Dec 14. pii: 2104. [Epub ahead of print]12(12):

Potential Role of Tumor-Derived Exosomes in Non-Small-Cell Lung Cancer in the Era of Immunotherapy.

Alfredo Tartarone, Rosa Lerose, Marina Tartarone, Michele Aieta.

  Lung cancer, of which non-small-cell lung cancer (NSCLC) represents about 80% of all cases, is the second most common cancer diagnosed in the general population and one of the major causes of cancer-related deaths worldwide. Overall, the outcomes of patients with advanced NSCLC are still disappointing despite advances in diagnosis and treatment. In recent years immune-checkpoint inhibitors (ICIs), administered alone or in combination with chemotherapy, have revolutionized the treatment landscape of patients with advanced non-small-cell lung cancer. However, until now, tissue expression of PD-L1 and tumor mutation burden represent the only available biomarkers for NSCLC patients treated with ICIs. A growing body of evidence showed that tumor-derived exosomes (TDEs) have the PD-L1 protein on their surface and that they are involved in angiogenesis, tumor growth, invasion, metastasis and immune escape. This review focused on the potential clinical applications of TDEs in NSCLC, including their possible role as a biomarker for prognosis and disease monitoring in patients undergoing immunotherapy.

Keywords:  exosomes; immune-checkpoint inhibitors; liquid biopsy; non-small-cell lung cancer; tumor-derived exosomes

DOI:  https://doi.org/10.3390/life12122104
Front Oncol. 2022 ;12 1056572

A tumor-associated autoantibody panel for the detection of non-small cell lung cancer.

Ruijun Cai, Feng Zhao, Haiying Zhou, Zengsong Wang, Dang Lin, Lu Huang, Wenling Xie, Jiawen Chen, Lamei Zhou, Ni Zhang, Chaoyuan Huang.

  Lung cancer is the second most frequent malignancy and the leading cause of cancer-associated death worldwide. Compared with patients diagnosed at advanced disease stages, early detection of lung cancer significantly improved the 5-year survival rate from 3.3% to 48.8%, which highlights the importance of early detection. Although multiple technologies have been applied to the screening and early diagnosis of lung cancer so far, some limitations still exist so they could not fully suit the needs for clinical application. Evidence show that autoantibodies targeting tumor-associated antigens(TAAs) could be found in the sera of early-stage patients, and they are of great value in diagnosis. Methods, we identified and screened TAAs in early-stage non-small cell lung cancer(NSCLC) samples using the serological analysis of recombinant cDNA expression libraries(SEREX). We measured the levels of the 36 autoantibodies targeting TAAs obtained by preliminary screening via liquid chip technique in the training set(332 serum samples from early-stage NSCLC patients, 167 samples from patients with benign lung lesions, and 208 samples from patients with no obvious abnormalities in lungs), and established a binary logistic regression model based on the levels of 8 autoantibodies to distinguish NSCLC samples. Results, We validated the diagnostic efficacy of this model in an independent test set(163 serum samples from early-stage NSCLC patients, and 183 samples from patients with benign lung lesions), the model performed well in distinguishing NSCLC samples with an AUC of 0.8194. After joining the levels of 4 serum tumor markers into its independent variables, the final model reached an AUC of 0.8568, this was better than just using the 8 autoantibodies (AUC:0.8194) or the 4 serum tumor markers alone(AUC: 0.6948). In conclusion, we screened and identified a set of autoantibodies in the sera of early-stage NSCLC patients through SEREX and liquid chip technique. Based on the levels of 8 autoantibodies, we established a binary logistic regression model that could diagnose early-stage NSCLC with high sensitivity and specificity, and the 4 conventional serum tumor markers were also suggested to be effective supplements for the 8 autoantibodies in the early diagnosis of NSCLC.

Keywords:  SEREX; TAAS; early diagnosis; liquid chip; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2022.1056572
Mol Ther. 2022 Dec 21. pii: S1525-0016(22)00715-8. [Epub ahead of print]

Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-cancer activity in MYC-overexpressing high-grade serous ovarian carcinoma.

Prahlad V Raninga, Yaowu He, Keshava K Datta, Xue Lu, Uma R Maheshwari, Pooja Venkat, Chelsea Mayoh, Harsha Gowda, Murugan Kalimutho, John D Hooper, Kum Kum Khanna.

Approximately 50-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. As MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, antioxidant signaling pathway along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with FDA-approved thioredoxin reductase-1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro, and also significantly reduced tumor growth in a MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.

DOI: https://doi.org/10.1016/j.ymthe.2022.12.011
Respir Res. 2022 Dec 19. 23(1): 362

HNRNPC, a predictor of prognosis and immunotherapy response based on bioinformatics analysis, is related to proliferation and invasion of NSCLC cells.

Zhuoyu Gu, Yang Yang, Qian Ma, Hui Wang, Song Zhao, Yu Qi, Yixin Li.

   BACKGROUND: Little is known about the relationship between N6-methyladenosine (m6A)-related genes and tumor immune microenvironment (TIME) in non-small cell lung cancer (NSCLC). It is unclear which m6A regulators are essential for NSCLC progression. The aim of this work was to excavate the role of m6A-related genes in the TIME and progression of NSCLC.
METHODS: Based on bioinformatics analysis, heterogeneous nuclear ribonucleoprotein C (HNRNPC) was considered as the most influential m6A regulator. Further study was investigated using patient samples, stable cell lines, and xenograft mice models.
RESULTS: The differentially expressed profiles of m6A-related genes were established in NSCLC, and the NSCLC samples were clustered into two subtypes with different immune infiltration and survival time. Next, we found that the risk score (RS) based on m6A-related genes was a predictor of prognosis and immunotherapy response for NSCLC, in which HNRNPC was considered as the most influential m6A regulator. In NSCLC patients, we confirmed that HNRNPC predicted poor prognosis and correlated with tumor invasion and lymph node metastasis. RNA-seq data revealed that HNRNPC was involved in cell growth, cell migration, extracellular matrix organization and angiogenesis. In vitro, we verified that HNRNPC knockdown attenuated the cell proliferation, clonogenicity, invasion and migration. In vivo, HNRNPC knockdown inhibited the tumor growth and lung metastasis. Additionally, HNRNPC knockdown was associated with high CD8 + T cell infiltration, along with elevated CD4 + T cell infiltration, collagen production and angiogenesis.
CONCLUSIONS: M6A regulator HNRNPC, a predictor of prognosis and immunotherapy response based on bioinformatics analysis, is related to proliferation and invasion of NSCLC cells.

Keywords:  HNRNPC; Invasion; NSCLC; Proliferation; m6A methylation

DOI:  https://doi.org/10.1186/s12931-022-02227-y
Genes (Basel). 2022 Dec 06. pii: 2295. [Epub ahead of print]13(12):

Identification of an Amino Acid Metabolism-Related Gene Signature for Predicting Prognosis in Lung Adenocarcinoma.

Wuguang Chang, Hongmu Li, Chun Wu, Leqi Zhong, Tengfei Zhu, Zenghao Chang, Wei Ou, Siyu Wang.

  Dysregulation of amino acid metabolism (AAM) is an important factor in cancer progression. This study intended to study the prognostic value of AAM-related genes in lung adenocarcinoma (LUAD). Methods: The mRNA expression profiles of LUAD datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied as the training and validation sets. After identifying the differentially expressed AAM-related genes, an AAM-related gene signature (AAMRGS) was constructed and validated. Additionally, we systematically analyzed the differences in immune cell infiltration, biological pathways, immunotherapy response, and drug sensitivity between the two AAMRGS subgroups. Results: The prognosis-related signature was constructed on the grounds of key AAM-related genes. LUAD patients were divided into AAMRGS-high and -low groups. Patients in the two subgroups differed in prognosis, tumor microenvironment (TME), biological pathways, and sensitivity to chemotherapy and immunotherapy. The area under the receiver operating characteristics (ROC) and calibration curves showed good predictive ability for the nomogram. Analysis of immune cell infiltration revealed that the TME of the AAMRGS-low group was in a state of immune activation. Conclusion: We constructed an AAMRGS that could effectively predict prognosis and guide treatment strategies for patients with LUAD.

Keywords:  amino acid metabolism; immunotherapy; lung adenocarcinoma; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3390/genes13122295
Eur J Pharmacol. 2022 Dec 16. pii: S0014-2999(22)00584-2. [Epub ahead of print] 175323

Metabolic reprogramming of glutamine involved in tumorigenesis, multidrug resistance and tumor immunity.

Wang Xiao-Yan, Yang Xiao-Xia, Shang Peng-Fei, Zheng Zong-Xue, Guo Xiu-Li.

  Glutamine, as the most abundant amino acid in the body, participates in the biological synthesis of nucleotides and other non-essential amino acids in the process of cell metabolism. Recent studies showed that glutamine metabolic reprogramming is an important signal during cancer development and progression. This metabolic signature in cancer cells can promote the development of cancer by activating multiple signaling pathways and oncogenes. It can also be involved in tumor immune regulation and promote the development of drug resistance to tumors. In this review, we mainly summarize the role of glutamine metabolic reprogramming in tumors, including the regulation of multiple signaling pathways. We further discussed the promising tumor treatment strategy by targeting glutamine metabolism alone or in combination with chemotherapeutics.

Keywords:  Glutamine; Multidrug resistance; Tumor immunotherapy; Tumor metabolism

DOI:  https://doi.org/10.1016/j.ejphar.2022.175323
Cell Death Dis. 2022 Dec 21. 13(12): 1064

Tumor immune microenvironment and immunotherapy efficacy in BRAF mutation non-small-cell lung cancer.

Hui Li, Yongchang Zhang, Yanjun Xu, Zhiyu Huang, Guoping Cheng, Mingyin Xie, Zichao Zhou, Yangyang Yu, Wenjing Xi, Yun Fan.

Previous small-size studies reported BRAF-mutated NSCLC patients have comparable sensitivity to immune checkpoint inhibitors (ICIs). However, how BRAF mutation affects the tumor immune microenvironment (TIME) is unknown. We performed Nanostring-panel RNA sequencing to evaluate TIME in 57 BRAF mutated and wild-type (WT) NSCLC specimens (cohort A). The efficacy of ICI monotherapy or combined therapies was determined in 417 patients with WT and BRAF mutated NSCLC (cohort B). We found that BRAF-mutant tumors had similar ratios of CD8+ T cells to Tregs, the balance of cytotoxicity gene expression signatures and immune suppressive features, and similar ICI-response-related biomarkers to WT NSCLC. A similar TIME pattern was observed between the BRAF V600E and Non-V600E subgroups of NSCLC. The further retrospective study confirmed that treatment with ICI monotherapy or combined therapies resulted in similar overall survival (OS) (HR: 0.85; 95% CI, 0.56 to 1.30; p = 0.47) and progress-free survival (PFS) (HR: 1.02; 95% CI, 0.72 to 1.44; p = 0.91) of patients with WT (n = 358) and BRAF mutant (n = 59) NSCLC. Similarly, both patients with BRAF V600E or Non-V600E NSCLC had similar responses to immunotherapy. Our findings support that BRAF mutation did not modulate TIME in NSCLC and therapeutic responses to ICIs. Patients with NSCLC harboring BRAF mutation should not be denied treatment with ICIs.

DOI: https://doi.org/10.1038/s41419-022-05510-4
Cell Cycle. 2022 Dec 19. 1-17

Prognostic value of RILPL2 and its correlation with tumor immune microenvironment and glycolysis in non-small cell lung cancer.

Dongfang Chen, Hongyan Zhang, Lifang Zhao, Xueqing Liu, Shan Xue, Peiling Wu, Handong Jiang.

  Rab-interacting lysosomal protein - like 2 (RILPL2) has been reported to be associated with prognosis and tumor biological functions in breast cancer and endometrial carcinoma. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. The expression and clinical data of lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) were downloaded from the TCGA database. The expression of RILPL2 in NSCLC cell lines was verified by the Western blot. We used online databases and bioinformatics analysis tools to explore its prognostic value, potential biological functions, and correlations with tumor immune microenvironment.The expression of RILPL2 was significantly lower in NSCLC compared with adjacent normal tissues. Low RILPL2 expression was associated with worse overall survival (OS) in NSCLC. The GO analysis showed RILPL2 was comprehensively involved in immune activity. RILPL2 expression was significantly positively correlated with the infiltration levels of B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, dendritic cells (P < 0.001), and it was also significantly positively correlated with programmed cell death ligand 1 (PD-L1/CD274) (P < 0.001). High RILPL2 expression could predict better immunotherapy response and prognosis in the immunotherapy cohort. The GSEA analysis showed low RILPL2 expression was associated with glycolysis process in LUAD, which was verified in vitro.These results showed RILPL2 expression was correlated with prognosis, tumor microenvironment, and immunotherapy response in NSCLC. Besides, RILPL2 may regulate glycolysis in LUAD.

Keywords:  NSCLC; RILPL2; glycolysis; prognosis; tumor immune microenvironment

DOI:  https://doi.org/10.1080/15384101.2022.2159203