bims-meluca 2023-02-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–02–26
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer.
Early Detection of Therapeutic Benefit from PD-1/PD-L1 Blockade in Advanced Lung Cancer by Monitoring Cachexia-Related Circulating Cytokines.
Quantitative proteomic analysis of bronchoalveolar lavage fluids from patients with small cell lung cancers.
Monitoring Blood Immune Cells in Patients with Advanced Small Cell Lung Cancer Undergoing a Combined Immune Checkpoint Inhibitor/Chemotherapy.
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
SOCS3 protein expression predicts the responses of advanced non-small cell lung cancer patients to platinum-based chemotherapy.
Circulating Biomarkers for Prediction of Immunotherapy Response in NSCLC.
A unique regulated cell death-related classification regarding prognosis and immune landscapes in non-small cell lung cancer.
The predictive value of plasma exosomal lncRNAs/mRNAs in NSCLC patients receiving immunotherapy.

Cancers (Basel). 2023 Feb 08. pii: 1076. [Epub ahead of print]15(4):

Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer.

Clelia Madeddu, Silvia Busquets, Clelia Donisi, Eleonora Lai, Andrea Pretta, Francisco Javier López-Soriano, Josep Maria Argilés, Mario Scartozzi, Antonio Macciò.

  Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

Keywords:  IL-6; NLR; cachexia; glasgow prognostic score; immune checkpoint inhibitor; immunotherapy; inflammation; miniCASCO; non-small cell lung cancer; sarcopenia; survival

DOI:  https://doi.org/10.3390/cancers15041076
Cancers (Basel). 2023 Feb 11. pii: 1170. [Epub ahead of print]15(4):

Early Detection of Therapeutic Benefit from PD-1/PD-L1 Blockade in Advanced Lung Cancer by Monitoring Cachexia-Related Circulating Cytokines.

Shiting Xu, Keita Miura, Takehito Shukuya, Sonoko Harada, Masahiro Fujioka, Wira Winardi, Shoko Shimamura, Kana Kurokawa, Issei Sumiyoshi, Taichi Miyawaki, Tetsuhiko Asao, Yoichiro Mitsuishi, Ken Tajima, Fumiyuki Takahashi, Takuo Hayashi, Norihiro Harada, Kazuhisa Takahashi.

  Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients.

Keywords:  cancer cachexia; circulating cytokines; immune checkpoint therapy; lung cancer; prognosis

DOI:  https://doi.org/10.3390/cancers15041170
Proteomics Clin Appl. 2023 Feb 21. e2300011

Quantitative proteomic analysis of bronchoalveolar lavage fluids from patients with small cell lung cancers.

Hung M Vu, Hazara Begum Mohammad, Thy N C Nguyen, Jun Hyung Lee, Yeji Do, Ji-Youn Sung, Seung Hyeun Lee, Min-Sik Kim.

   PURPOSE: Small cell lung cancer (SCLC) is one of the malignant cancers with aggressive progression and poor prognosis. Bronchoalveolar lavage fluid (BALF) has been arising recently as a potential source of biomarkers for lung cancers. In this study, we performed quantitative BALF proteomic analysis to identify potential biomarkers for SCLC.
EXPERIMENTAL DESIGN: BALF were collected from tumor-bearing lungs and non-tumor lungs of five SCLC patients. Then, BALF proteomes were prepared for a TMT-based quantitative mass spectrometry analysis. Differentially expressed proteins were identified when considering individual variation. Potential SCLC biomarker candidates were validated by immunohistochemistry. A public database of multiple SCLC cell lines was used to evaluate the correlation of these markers with SCLC subtypes and chemo-drug responses.
RESULTS: We identified 460 BALF proteins in SCLC patients and observed considerable individual variation among the patients. Immunohistochemical analysis and bioinformatics resulted in the identification of CNDP2 and RNPEP as potential subtype markers for ASCL1 and NEUROD1, respectively. In addition, CNDP2 was found to be positively correlated with responses to etoposide, carboplatin, and irinotecan.
CONCLUSIONS AND CLINICAL RELEVANCE: BALF is an emerging source of biomarkers, making it useful for the diagnosis and prognosis of lung cancers. We characterized the proteomes of paired BALF samples collected from tumor-bearing and non-tumor lungs of SCLC patients. Several proteins were found elevated in tumor-bearing BALF, and especially CNDP2 and RNPEP appeared to be potential indicators for ASLC1-high and NEUROD1-high subtypes of SCLC, respectively. The positive correlation of CNDP2 with chemo-drug responses would help to make decisions for treatment of SCLC patients. These putative biomarkers could be comprehensively investigated for a clinical use towards precision medicine. This article is protected by copyright. All rights reserved.

Keywords:  Proteomics; SCX StageTips; TMT labeling; bronchoalveolar lavage fluid; small cell lung cancer

DOI:  https://doi.org/10.1002/prca.202300011
Biomolecules. 2023 Jan 17. pii: 190. [Epub ahead of print]13(2):

Monitoring Blood Immune Cells in Patients with Advanced Small Cell Lung Cancer Undergoing a Combined Immune Checkpoint Inhibitor/Chemotherapy.

Dagmar Riemann, Steffi Turzer, Georgi Ganchev, Wolfgang Schütte, Barbara Seliger, Miriam Möller.

  In this exploratory prospective observational study on 40 small cell lung cancer (SCLC) patients treated with a combination of chemotherapy and immune checkpoint inhibitors, blood immune cells were characterized by multi-color flow cytometry at the baseline and at the third therapy cycle. The numbers of neutrophils and of T-, B-, and NK cells, as well as the frequency of HLA-DRlow monocytes, 6-SulfoLacNAc (slan)+ non-classical monocytes and circulating dendritic cell (DC) subtypes were determined. The prognostic value of the parameters was evaluated by the patient's survival analysis with overall survival (OS) as the primary endpoint. In addition, blood cell parameters from SCLC patients were compared to those from non-SCLC (NSCLC). The global median OS of patients was 10.4 ± 1.1 months. Disease progression (15% of patients) correlated with a higher baseline neutrophil/lymphocyte ratio (NLR), more HLA-DRlow monocytes, and lower NK cell and DC numbers. The risk factors for poor OS were the presence of brain/liver metastases, a baseline NLR ≥ 6.1, HLA-DRlow monocytes ≥ 21% of monocytes, slan+ non-classical monocytes < 0.12%, and/or CD1c+ myeloid DC < 0.05% of leukocytes. Lymphocytic subpopulations did not correlate with OS. When comparing biomarkers in SCLC versus NSCLC, SCLC had a higher frequency of brain/liver metastases, a higher NLR, the lowest DC frequencies, and lower NK cell numbers. Brain/liver metastases had a substantial impact on the survival of SCLC patients. At the baseline, 45% of SCLC patients, but only 24% of NSCLC patients, had between three and five risk factors. A high basal NLR, a high frequency of HLA-DRlow monocytes, and low levels of slan+ non-classical monocytes were associated with poor survival in all lung cancer histotypes. Thus, the blood immune cell signature might contribute to a better prediction of SCLC patient outcomes and may uncover the pathophysiological peculiarities of this tumor entity.

Keywords:  HLA-DRlow monocytes; biomarker; dendritic cells; immune checkpoint inhibitor; immune monitoring; neutrophil/lymphocyte ratio; overall survival; slan+ non-classical monocytes; small-cell lung cancer

DOI:  https://doi.org/10.3390/biom13020190
bioRxiv. 2023 Feb 18. pii: 2023.02.17.528937. [Epub ahead of print]

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R Flint, Claire M Connell, Michael Lukey, Eileen P White, Anthony P Coll, Ashok R Venkitaraman, Tobias Janowitz.

The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

DOI: https://doi.org/10.1101/2023.02.17.528937
Ann Transl Med. 2023 Jan 31. 11(2): 94

SOCS3 protein expression predicts the responses of advanced non-small cell lung cancer patients to platinum-based chemotherapy.

Xiao-Ming Zhang, Tian-Yang Liu, Shi-Qi Li, Xin-Ai Han, Rui Song, Jin-Hong Wang.

   Background: This study sought to assess the relationship between suppressor of cytokine signaling 3 (SOCS3) expression, SOCS3 promoter methylation status, and platinum-based chemotherapy responses in advanced non-small cell lung cancer (NSCLC) patients.
Methods: A total of 400 advanced NSCLC patients with inoperable disease were enrolled in this study. All the patients underwent platinum-based chemotherapy treatment, and the clinical and prognostic outcomes of these patients were analyzed. The SOCS3 protein expression and SOCS3 promoter methylation status of the tumor tissues in these patients were also tested by immunohistochemistry and polymerase chain reaction (PCR), respectively. In addition, we knocked down SOCS3 expression via small-interfering RNA (siRNA) in the lung cancer cell lines and conducted in vitro analyses to examine cell viability and apoptosis.
Results: Patients with higher expression levels of SOCS3 were found to have a lower average tumor stage, higher average tumor differentiation, and higher rates of positive chemotherapy responses than those with lower expression levels of SOCS3. SOCS3 promoter methylation was also found to be correlated with chemotherapy responses in these patients. In the prognostic analyses, only SOCS3 expression, but not SOCS3 promoter methylation, was found to be predictive of outcomes in advanced NSCLC patients. We also found that the pro-apoptotic effects of SOCS3 were mediated by the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways in the lung cancer cells.
Conclusions: Currently, there is a lack of reliable biomarkers for predicting the responses of NSCLC patients to chemotherapy. Our results may aid in clinical evaluations of NSCLC patients.

Keywords:  Suppressor of cytokine signaling 3 (SOCS3); non-small cell lung cancer (NSCLC); promoter methylation; treatment response

DOI:  https://doi.org/10.21037/atm-22-6065
Biomedicines. 2023 Feb 09. pii: 508. [Epub ahead of print]11(2):

Circulating Biomarkers for Prediction of Immunotherapy Response in NSCLC.

Kah Yee Goh, Terence You De Cheng, Su Chin Tham, Darren Wan-Teck Lim.

  Non-small cell lung cancer (NSCLC) constitutes the majority of the lung cancer population and the prognosis is poor. In recent years, immunotherapy has become the standard of care for advanced NSCLC patients as numerous trials demonstrated that immune checkpoint inhibitors (ICI) are more efficacious than conventional chemotherapy. However, only a minority of NSCLC patients benefit from this treatment. Therefore, there is an unmet need for biomarkers that could accurately predict response to immunotherapy. Liquid biopsy allows repeated sampling of blood-based biomarkers in a non-invasive manner for the dynamic monitoring of treatment response. In this review, we summarize the efforts and progress made in the identification of circulating biomarkers that predict immunotherapy benefit for NSCLC patients. We also discuss the challenges with future implementation of circulating biomarkers into clinical practice.

Keywords:  biomarkers; checkpoint inhibition; immunotherapy; liquid biopsy; lung cancer

DOI:  https://doi.org/10.3390/biomedicines11020508
Front Immunol. 2023 ;14 1075848

A unique regulated cell death-related classification regarding prognosis and immune landscapes in non-small cell lung cancer.

Wei Su, Ting Hong, Baijie Feng, Zhou Yang, Guang Lei.

  Regulated cell death (RCD) contributes to reshaping the tumor immune microenvironment and participating in the progression of non-small cell lung cancer (NSCLC); however, related mechanisms have not been fully disclosed. Here, we identified 5 subclusters of NSCLC based on consensus clustering of 3429 RCD-associated genes in the TCGA database and depicted the genomic features and immune landscape of these clusters. Importantly, the clusters provided insights into recognizing tumor microenvironment (TME) and tumor responses to immunotherapy and chemotherapy. Further, we established and validated an RCD-Risk model based on RCD-associated genes, which strongly predicted the prognosis, TME, and immunotherapy outcomes in NSCLC patients. Notably, tissue microarray staining confirmed that the expression of LDLRAD3, a core gene in RCD-Risk model, correlated with poor survival. In conclusion, we developed a novel RCD classification system and RCD-Risk model of NSCLC, serving as a robust and promising predictor for prognosis and immunotherapy benefit of individual NSCLC patients.

Keywords:  immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; regulated cell death; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1075848
Adv Med Sci. 2023 Feb 17. pii: S1896-1126(23)00003-2. [Epub ahead of print]68(1): 86-93

The predictive value of plasma exosomal lncRNAs/mRNAs in NSCLC patients receiving immunotherapy.

Yue Wang, Shuhui Cao, Jingwen Li, Yao Zhang, Xuxinyi Ling, Lincheng Zhang, Yan Zhou, Hua Zhong.

   PURPOSE: There is an urgent need to explore the use of plasma-derived exosomal long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) as potential biomarkers to select the most suitable patient population to receive immunotherapy for advanced NSCLC with no actionable molecular markers.
PATIENTS AND METHODS: In the present study, 7 patients with advanced NSCLC who received nivolumab were enrolled for molecular studies. Plasma-derived exosomal lncRNAs/mRNAs expression profiles differed between patients exhibiting differential immunotherapy efficacy.
RESULTS: In the non-responders, 299 differentially expressed exosomal mRNAs and 154 lncRNAs were significantly upregulated. In GEPIA2, 10 mRNAs were upregulated in the NSCLC patients compared to that of the normal population. The up-regulation of CCNB1 related to the cis-regulation of lnc-CENPH-1 and lnc-CENPH-2. KPNA2, MRPL3, NET1 and CCNB1 were trans-regulated by lnc-ZFP3-3. In addition, IL6R exhibited a trend of increased expression in the non-responders at baseline, and this expression was further downregulated after treatment in responders. The association between CCNB1 with lnc-CENPH-1 and lnc-CENPH-2, as well as the lnc-ZFP3-3-TAF1 pair, may represent potential biomarkers of poor immunotherapy efficacy. Patients may obtain increased effector T cell function when IL6R is suppressed by immunotherapy.
CONCLUSIONS: Our study suggests that plasma-derived exosomal lncRNA and mRNA expression profiles differ between responders and non-responders to nivolumab immunotherapy. Lnc-ZFP3-3-TAF1-CCNB1 pair and IL6R might be key factors predicting efficiency of immunotherapy. Large scale clinical studies seem warranted to further validate the potential of plasma-derived exosomal lncRNAs and mRNAs as a biomarker to aid the selection of NSCLC patients for nivolumab immunotherapy.

Keywords:  Exosomes; Immunotherapy; Lung cancer; lncRNA; mRNA

DOI:  https://doi.org/10.1016/j.advms.2023.01.003