bims-meluca 2024-12-22 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–12–22
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.
Predictive Value of T-Lymphocyte Subsets in Combination with Serum Tumour Markers for Prognosis of Patients with Non-Small Cell Lung Cancer Undergoing Chemotherapy.
Association Between Body Mass Index and Survival in Patients with De Novo Metastatic Non-Small Cell Lung Cancer.
LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer.
Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.
Sex-Specific Effects of Body Composition on Tumor Microenvironment in Non-Small Cell Lung Cancer: Obesity, Gender, and TME in NSCLC.
Immune-related adverse events correlate with the clinical efficacy in advanced Non-Small-Cell Lung Cancer patients treated with PD-1 inhibitors combination therapy.
Plasma metabolomics profiling of EGFR-mutant NSCLC patients treated with third-generation EGFR-TKI.
Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.

Oncoimmunology. 2025 Dec;14(1): 2442116

Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy.

Hayato Kawachi, Tadaaki Yamada, Motohiro Tamiya, Yoshiki Negi, Takashi Kijima, Yasuhiro Goto, Akira Nakao, Shinsuke Shiotsu, Keiko Tanimura, Takayuki Takeda, Asuka Okada, Taishi Harada, Koji Date, Yusuke Chihara, Isao Hasegawa, Nobuyo Tamiya, Yuki Katayama, Naoya Nishioka, Kenji Morimoto, Masahiro Iwasaku, Shinsaku Tokuda, Takayuki Shimose, Koichi Takayama.

  This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Keywords:  Cancer cachexia; combination therapy; immune checkpoint inhibitor; non-small cell lung cancer; treatment outcome

DOI:  https://doi.org/10.1080/2162402X.2024.2442116
Folia Biol (Praha). 2024 ;70(4): 189-195

Predictive Value of T-Lymphocyte Subsets in Combination with Serum Tumour Markers for Prognosis of Patients with Non-Small Cell Lung Cancer Undergoing Chemotherapy.

Jinfeng Zhang.

  We aimed to detect the levels of T-lympho-cyte subsets and serum tumour markers in patients with non-small cell lung cancer (NSCLC) before chemotherapy, and to investigate the predictive value of their combined detection for the prognosis of NSCLC patients undergoing chemotherapy. The clinical data of 110 NSCLC patients treated with chemotherapy from January 2019 to February 2021 were analysed retrospectively. All patients were followed up for one year and divided into good prognosis group (surviving cases) and poor prognosis group (deceased cases). The predictive value of T-lymphocyte subsets combined with serum tumour markers for prognosis was analysed. The proportions of patients with tumour-node-metastasis stages III-IV, lymph node metastasis and poor differentiation were higher in the poor prognosis group than those in the good prognosis group (P < 0.05). Cox regression analysis revealed that high expression of CD4+ and CEA represented protective factors for poor prognosis of NSCLC patients undergoing chemotherapy [odds ratio (OR) < 1, P < 0.05], while high expression of CA125 was a risk factor (OR > 1, P < 0.05). All the areas under the receiver operating characteristic curves of single indicator detection (CD4+, CEA and CA125 levels) and their combined detection for prediction of the poor prognosis of NSCLC patients undergoing chemotherapy were > 0.70, which was highest in the case of combined detection. T-lymphocyte subsets and serum tumour markers are closely related to the prognosis of NSCLC patients undergoing chemotherapy, and their combined detection is of high predictive value.

Keywords:  T-lymphocyte subset; non-small cell lung cancer; prediction; prognosis; tumour marker

DOI:  https://doi.org/10.14712/fb2024070040189
Med Sci Monit. 2024 Dec 18. 30 e946751

Association Between Body Mass Index and Survival in Patients with De Novo Metastatic Non-Small Cell Lung Cancer.

Muslih Ürün, Gürkan Güner, Yasin Sezgin, Abdullah Sakin, Saadettin Kılıçkap.

BACKGROUND This retrospective study from a single center included 289 patients diagnosed with advanced non-small cell lung cancer (NSCLC) between 2010 to 2017 and aimed to evaluate the effects of body mass index (BMI) on overall survival. MATERIAL AND METHODS This retrospective study involved 289 patients diagnosed with metastatic-stage NSCLC at a single institution between January 2010 and December 2017. Patients were categorized into 2 groups based on their BMI at diagnosis: those with a BMI <25 kg/m² and those with a BMI ≥25 kg/m². Univariate and multivariate Cox regression analyses were conducted to identify factors associated with overall survival. RESULTS A total of 289 patients (241 men, 48 women) were included in the study, with a mean age of 60.1±11.1 years. Among them, 175 patients (60.6%) had a BMI less than 25 kg/m². Multivariate analysis revealed that BMI, pathological diagnosis, and complete response after first-line treatment were independently associated with survival in patients with lung cancer. Predicted survival time was significantly shorter in the BMI <25 group than in the BMI ≥25 group (9.3 months vs 13.0 months, P<0.05). CONCLUSIONS The study demonstrated that a higher BMI at the time of diagnosis is associated with improved overall survival in patients with de novo metastatic NSCLC. BMI may serve as an important prognostic factor in this patient population. Future prospective, multi-center studies are necessary to further validate the role of BMI in predicting survival outcomes in NSCLC patients across different treatment modalities.

DOI: https://doi.org/10.12659/MSM.946751
J Immunother Cancer. 2024 Dec 18. pii: e009444. [Epub ahead of print]12(12):

LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer.

Liting Lv, Qing Miao, Sutong Zhan, Peilin Chen, Wei Liu, Jiawen Lv, Wenjie Yan, Dong Wang, Hongbing Liu, Jie Yin, Jian Feng, Yong Song, Mingxiang Ye, Tangfeng Lv.

   BACKGROUND: Loss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood. In this study, we deciphered how LKB1 regulated sensitivity to anti-PD-1/PD-L1 immunotherapy.
METHODS: We investigated the mutational landscape of LKB1 mutant NSCLC in next generation sequencing (NGS) data sets. Expression of LKB1, PD-L1 and S-phase kinase-associated protein 2 (Skp2) in NSCLC samples were assessed by immunohistochemistry (IHC). The tumor microenvironment (TME) profiling of LKB1 wild type (WT) and mutant NSCLC was performed using fluorescent multiplex IHC. Mass spectrometry and enrichment analysis were used to identify LKB1 interacting proteins. Mechanistic pathways were explored by immunoblotting, ubiquitination assay, cycloheximide chase assay and immunoprecipitation assay.
RESULTS: By using NGS data sets and histological approaches, we demonstrated that LKB1 status was positively associated with PD-L1 protein expression and conferred a T cell-enriched "hot" TME in NSCLC. Patients with good responses to anti-PD-1/PD-L1 immunotherapy possessed a high level of LKB1 and PD-L1. Skp2 emerged as the molecular hub connecting LKB1 and PD-L1, by which Skp2 catalyzed K63-linked polyubiquitination on K136 and K280 residues to stabilize PD-L1 protein. Inhibition of Skp2 expression by short hairpin RNA or its E3 ligase activity by compound #25 abrogated intact expression of PD-L1 in vitro and generated a T cell-excluded "cold" TME in vivo. Thus, the LKB1-Skp2-PD-L1 regulatory loop was crucial for retaining PD-L1 protein expression and manipulation of this pathway would be a feasible approach for TME remodeling.
CONCLUSION: LKB1 and Skp2 are required for intact PD-L1 protein expression and TME remodeling in NSCLC. Inhibition of Skp2 resulted in a conversion from "hot" TME to "cold" TME and abrogated therapeutic outcomes of immunotherapy. Screening LKB1 and Skp2 status would be helpful to select recipients who may benefit from anti-PD-1/PD-L1 immunotherapy.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Lung Cancer; Next generation sequencing - NGS; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2024-009444
Nat Commun. 2024 Dec 17. 15(1): 10484

Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.

Hannah E Greenwood, Abigail R Barber, Richard S Edwards, Will E Tyrrell, Madeleine E George, Sofia N Dos Santos, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P Ward, Janine M DeBlasi, Laura Torrente, Pritin N Soni, David R Pearce, George Firth, Lydia M Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Charles Swanton, Robert E Hynds, Gina M DeNicola, Timothy H Witney.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

DOI: https://doi.org/10.1038/s41467-024-54852-4
Ann Thorac Surg Short Rep. 2023 Sep;1(3): 465-468

Sex-Specific Effects of Body Composition on Tumor Microenvironment in Non-Small Cell Lung Cancer: Obesity, Gender, and TME in NSCLC.

Yeshwanth Vedire, Robert Seager, Erik Van Roey, Shuang Gao, Mary Nesline, Jeffrey Conroy, Grace Dy, Joseph Barbi, Sarabjot Pabla, Sai Yendamuri.

Background: There exists a gap in understanding the interaction between sex and obesity on tumor microenvironment in NSCLC. We demonstrate the combined effects of sex and body composition on clinically relevant biomarkers of NSCLC immune response.
Methods: A cohort of 409 patients with NSCLC was subdivided into 4 groups jointly defined by body mass index (BMI; cutoff of 25 kg/m2) and sex (male-high BMI, male-low BMI, female-high BMI, female-low BMI). Associations between these sex-BMI groups and tumor inflammation (expression of 161 immune response genes), cell proliferation (expression of 10 cell proliferation genes), and programmed cell death ligand 1 (PD-L1; through immunohistochemistry and targeted RNA sequencing) were assessed by Kruskal-Wallis and Wilcoxon rank sum tests for overall and pairwise tests, respectively.
Results: We observed an overall significant association of sex-BMI with tumor inflammation (P < .001) and cell proliferation (P = .002). On pairwise analysis, high-BMI females had significantly higher tumor inflammation compared with low-BMI females (P = .002). In addition, women with a high (P = .004) and low (P = .008) BMI had significantly higher tumor inflammation compared with men with a high and low BMI, respectively. Low-BMI females (P = .01) and males (P = .01) had more cell proliferation. PD-L1 expression by RNA sequencing (P = .001) but not by immunohistochemical analysis differed significantly with sex-BMI. High-BMI females had significantly higher PD-L1 expression compared with low-BMI females (P = .01).
Conclusions: We demonstrate that tumor inflammation and PD-L1 expression are more strongly associated with BMI in women than in men. Additional studies are required to better understand the mechanisms underlying these effects and their role in response to checkpoint inhibitors in NSCLC.

DOI: https://doi.org/10.1016/j.atssr.2023.05.012
BMC Cancer. 2024 Dec 18. 24(1): 1541

Immune-related adverse events correlate with the clinical efficacy in advanced Non-Small-Cell Lung Cancer patients treated with PD-1 inhibitors combination therapy.

Xiaowan Xie, Yuhao Li, Qiaomei Lv, Wei Wang, Wenbo Ding, Yuanyuan Li.

   OBJECTIVE: The potential of immune-related adverse events (irAEs) in predicting the efficacy of PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) has rarely been assessed. This study investigated the associations between irAEs and the clinical efficacy of PD-1 inhibitors combination therapy in patients with advanced NSCLC.
METHODS: A retrospective analysis was conducted of 73 patients with advanced NSCLC receiving PD-1 inhibitors combination therapy from January 2022 and July 2023. Patients were divided into two cohorts: patients with irAEs and patients without irAEs. We conducted an analysis to investigate the impact of irAEs on these different clinical outcomes.
RESULTS: There were no significant differences observed in clinical characteristics between the two cohorts, except for smoking status (P = 0.011).The cohort with irAEs exhibited a higher objective response rate (ORR) and disease control rate (DCR) compared to the cohort without irAEs (ORR: 32.5% vs 12.1%, P = 0.040; DCR: 80.0% vs 48.5%, P = 0.010).Moreover, the median progression-free survival (PFS) and overall survival (OS) were significantly better in the cohort with irAEs compared to the cohort without irAEs (PFS: 12.4 months vs 6.8 months, P = 0.009; OS: not reached vs 18.3 months, P = 0.024). Additionally, the multivariate COX regression analysis revealed that mild irAEs (PFS: HR = 0.386, 95% CI: 0.199-0.748, P = 0.005; OS: HR = 0.300, 95% CI: 0.105-0.855, P = 0.024) and single-system irAEs (PFS: HR = 0.401, 95% CI: 0.208-0.772, P = 0.006; OS: HR = 0.264, 95% CI: 0.090-0.776, P = 0.015) were identified as independent prognostic factors for both PFS and OS.
CONCLUSIONS: IrAEs, especially thyroid irAEs, as well as mild or single-system irAEs, may serve as predictors of improved efficacy in advanced NSCLC patients receiving PD-1 inhibitors combination therapy.

Keywords:  Advanced non; Cell lung cancer; Clinical efficacy; Immune related adverse events; PD- 1 inhibitors combination therapy; Small

DOI:  https://doi.org/10.1186/s12885-024-13220-7
Sci Data. 2024 Dec 18. 11(1): 1369

Plasma metabolomics profiling of EGFR-mutant NSCLC patients treated with third-generation EGFR-TKI.

Ning Lou, Ruyun Gao, Yuankai Shi, Xiaohong Han.

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies.

DOI: https://doi.org/10.1038/s41597-024-04169-0
Extracell Vesicles Circ Nucl Acids. 2024 ;5(3): 371-396

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.

Cátia C Ramos, José Pires, Esperanza Gonzalez, Clara Garcia-Vallicrosa, Celso A Reis, Juan M Falcon-Perez, Daniela Freitas.

  Cancer cachexia is a complex metabolic syndrome characterized by unintentional loss of skeletal muscle and body fat. This syndrome is frequently associated with different types of cancer and negatively affects the prognosis and outcome of these patients. It involves a dynamic interplay between tumor cells and adipose tissue, where tumor-derived extracellular vesicles (EVs) play a crucial role in mediating intercellular communication. Tumor cells release EVs containing bioactive molecules such as hormones (adrenomedullin, PTHrP), pro-inflammatory cytokines (IL-6), and miRNAs (miR-1304-3p, miR-204-5p, miR-155, miR-425-3p, miR-146b-5p, miR-92a-3p), which can trigger lipolysis and induce the browning of white adipocytes contributing to a cancer cachexia phenotype. On the other hand, adipocyte-derived EVs can reprogram the metabolism of tumor cells by transporting fatty acids and enzymes involved in fatty acid oxidation, resulting in tumor growth and progression. These vesicles also carry leptin and key miRNAs (miR-155-5p, miR-10a-3p, miR-30a-3p, miR-32a/b, miR-21), thereby supporting tumor cell proliferation, metastasis formation, and therapy resistance. Understanding the intricate network underlying EV-mediated communication between tumor cells and adipocytes can provide critical insights into the mechanisms driving cancer cachexia. This review consolidates current knowledge on the crosstalk between tumor cells and adipose tissue mediated by EVs and offers valuable insights for future research. It also addresses controversial topics in the field and possible therapeutic approaches to manage cancer cachexia and ultimately improve patient outcomes and quality of life.

Keywords:  Cancer cachexia; adipose tissue transdifferentiation; cancer; exosome; extracellular vesicles; metabolism

DOI:  https://doi.org/10.20517/evcna.2024.36