bims-meluca 2024-07-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–07–28
twelve papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma.
The association of nutritional and inflammatory biomarkers with overall survival in patients with non-small-cell lung cancer treated with immune checkpoint inhibitors.
Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.
Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer.
Sarcopenia as a Predictive Factor for Carboplatin Toxicity in Patients with Advanced Non-Small Cell Lung Cancer.
CXCL5 impedes CD8+ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis.
Prognostic value of immunotherapy in advanced non-small cell lung cancer based on baseline and dynamic changes in hemoglobin, albumin, and platelets.
Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital.
Circulating levels of galectin-9 are a potential biomarker of survival in advanced non-small-cell lung cancer.
The 3D organ-on-a-chip model unveils a dual role of GDF-15 in vascular growth.
Deciphering the prognostic role of endoplasmic reticulum stress in lung adenocarcinoma: integrating prognostic prediction and immunotherapy strategies.
PPAR-γ/NF-kB/AQP3 axis in M2 macrophage orchestrates lung adenocarcinoma progression by upregulating IL-6.

PLoS One. 2024 ;19(7): e0307580

Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma.

Yao Liang, Osamu Maeda, Chiaki Kondo, Kazuki Nishida, Yuichi Ando.

BACKGROUND: This study aimed to identify the associations between individual KRAS, STK11, KEAP1, or TP53 mutations, as well as the comutation status of these genes, and the tumor mutation burden (TMB) with clinical outcomes of lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs).
METHODS: We collected data from patients with lung adenocarcinoma treated with ICIs from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and August 2023. The main endpoints were the treatment response and overall survival (OS).
RESULTS: Among 343 patients with lung adenocarcinoma, 61 (18%), 69 (20%), 41 (12%), and 222 (65%) patients had KRAS, STK11, KEAP1, and TP53 mutations, respectively. An overall objective response was observed in 94 of 338 patients (28%), including 2 (1%) who achieved a complete response and 92 (27%) who achieved a partial response. Patients with STK11, KEAP1, or TP53 mutations had a significantly greater TMB (P<0.001). According to the univariate analysis, the treatment response was significantly correlated with TP53 mutation in both the general (P = 0.041) and KRAS wild-type (P = 0.009) populations. KEAP1 and TP53 mutations were associated with worse OS among assessable patients (hazard ratio (HR) = 2.027, P = 0.002; HR = 1.673, P = 0.007, respectively) and among patients without KRAS mutations (HR = 1.897, P = 0.012; HR = 1.908, P = 0.004, respectively). According to the multivariate analysis, KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were found to be independent factors for OS.
CONCLUSIONS: STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB. TP53 mutation could affect the treatment response to some degree, and both KEAP1 and TP53 mutations resulted in inferior OS in the general patient population and in those with KRAS-wild-type lung adenocarcinoma, indicating that KEAP1 and TP53 mutations might act as prognostic factors for ICI treatment in lung adenocarcinoma patients.

DOI: https://doi.org/10.1371/journal.pone.0307580
Thorac Cancer. 2024 Jul 19.

The association of nutritional and inflammatory biomarkers with overall survival in patients with non-small-cell lung cancer treated with immune checkpoint inhibitors.

I M Horstman, P C Vinke, E Suazo-Zepeda, T J N Hiltermann, M A Heuvelmans, E Corpeleijn, G H de Bock.

   OBJECTIVES: Pretreatment biomarkers are needed to identify patients with non-small-cell lung cancer (NSCLC) likely to have worse survival. This ensures that only patients with a real chance of benefit receive immune checkpoint inhibitor (ICI) treatment. In this study, we examined the associations of baseline nutritional and inflammatory biomarkers with overall survival in a real-world cohort of NSCLC patients who received ICIs.
MATERIALS AND METHODS: We used prospectively collected data from the OncoLifeS data biobank. The cohort included 500 advanced-stage NSCLC patients treated with ICIs from May 2015 to June 2021. Biomarkers were evaluated within 2 weeks before ICI treatment: neutrophil-to-lymphocyte ratio, C-reactive protein (CRP), Glasgow prognostic score, CRP/albumin ratio (CAR), prognostic nutritional index (PNI), and advanced lung cancer inflammation index. For each biomarker, low- and high-risk groups were defined using literature-based cut-offs. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were estimated using adjusted survival analysis.
RESULTS: Most patients were male (60.8%), the mean baseline age was 65 ± 9 years, and 88% had stage IV disease. For each biomarker, low-risk patients had better overall survival (all, p < 0.001), with CAR and PNI showing the strongest associations. In multivariable analyses a combined CAR/PNI risk score had a stronger association with overall survival (aHR 3.09, 95% CI 2.36-4.06) than CAR alone (aHR 2.22, 95% CI 1.79-2.76) or PNI alone (aHR 2.09, 95% CI 1.66-2.61).
CONCLUSION: These results highlight the potential value of nutritional and inflammatory biomarkers, in particular CAR and PNI, in identifying NSCLC patients with highest mortality risk before starting ICI treatment.

Keywords:  immune checkpoint inhibitors; immunotherapy; non‐small‐cell lung cancer; nutritional and inflammatory biomarkers; prognostic markers

DOI:  https://doi.org/10.1111/1759-7714.15401
Eur J Clin Invest. 2024 Jul 26. e14288

Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

Willian das Neves, Christiano R R Alves, Gabriela Dos Santos, Maria-Janieire N N Alves, Amy Deik, Kerry Pierce, Courtney Dennis, Lily Buckley, Clary B Clish, Kathryn J Swoboda, Patricia C Brum, Gilberto de Castro Junior.

   BACKGROUND: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells.
METHODS: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis.
RESULTS: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance.
CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

Keywords:  cancer cachexia; metabolomics; myotubes; non‐small cell lung cancer; skeletal muscle wasting

DOI:  https://doi.org/10.1111/eci.14288
Front Oncol. 2024 ;14 1348164

Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer.

Hui Jiang, Xu-Shuo Li, Ying Yang, Rui-Xue Qi.

   Background: Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with chemo-immunotherapy emerging as a promising approach. This study explores the potential of lipidomic biomarkers to predict responses to chemo-immunotherapy in advanced non-small cell lung cancer (NSCLC) patients.
Methods: A prospective analysis was conducted on 68 NSCLC patients undergoing chemo-immunotherapy, divided into disease control (DC) and progressive disease (PD) groups based on treatment response. Pre-treatment serum samples were subjected to lipidomic profiling using liquid chromatography-mass spectrometry (LC-MS). Key predictive lipids (biomarkers) were identified through projection to latent structures discriminant analysis. A biomarker combined model and a clinical combined model were developed to enhance the prediction accuracy. The predictive performances of the clinical combined model in different histological subtypes were also performed.
Results: Six lipids were identified as the key lipids. The expression levels of PC(16:0/18:2), PC(16:0/18:1), PC(16:0/18:0), CE(20:1), and PC(14:0/18:1) were significantly up-regulated. While the expression level of TAG56:7-FA18:2 was significantly down-regulated. The biomarker combined model demonstrated a receiver operating characteristic (ROC) curve of 0.85 (95% CI: 0.75-0.95) in differentiating the PD from the DC. The clinical combined model exhibited an AUC of 0.87 (95% CI: 0.79-0.96) in differentiating the PD from the DC. The clinical combined model demonstrated good discriminability in DC and PD patients in different histological subtypes with the AUC of 0.78 (95% CI: 0.62-0.96), 0.79 (95% CI: 0.64-0.94), and 0.86 (95% CI: 0.52-1.00) in squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtype, respectively. Pathway analysis revealed the metabolisms of linoleic acid, alpha-linolenic acid, glycerolipid, arachidonic acid, glycerophospholipid, and steroid were implicated in the chemo-immunotherapy response in advanced NSCLC.
Conclusion: Lipidomic profiling presents a highly accurate method for predicting responses to chemo-immunotherapy in patients with advanced NSCLC, offering a potential avenue for personalized treatment strategies.

Keywords:  LC-MS; biomarker; chemo-immunotherapy; lipidomics; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2024.1348164
Nutr Cancer. 2024 Jul 26. 1-9

Sarcopenia as a Predictive Factor for Carboplatin Toxicity in Patients with Advanced Non-Small Cell Lung Cancer.

Jenny G Turcott, Sayako M Miyagui, Salvador Gutiérrez Torres, Daniela Cárdenas-Fernández, Enrique Caballé-Perez, Eduardo Rios-Garcia, Andrés F Cardona, Christian Rolfo, Oscar Arrieta.

Sarcopenia in cancer patients often negatively impacts various outcomes. Carboplatin, a first-line chemotherapy for non-small cell lung cancer (NSCLC), is dosed based on body weight, which doesn't account for sarcopenia. This study evaluated the association between sarcopenia and carboplatin-related toxicity in NSCLC patients. Patients with locally advanced or metastatic NSCLC treated with carboplatin were included. Toxicity events during the first two cycles of treatment were recorded. Sarcopenia was assessed using pretreatment computed tomography scans analyzed with Slice-O-Matic V4.2 software, defining sarcopenia as a skeletal muscle index (SMI) of <52.4 cm2/m2 for men and <38.5 cm2/m2 for women. Among 146 patients, 52% had sarcopenia. Hematological toxicity occurred in 71.2% of all patients and 77.6% of those with sarcopenia. The fat-free mass index (FFMI) was independently associated with hematological toxicity and dose-limiting toxicity (DLT), which was observed in 55.5% of patients. Sarcopenia significantly correlates with hematological toxicity and DLT during carboplatin treatment in NSCLC patients. Given its prevalence and noninvasive detection, further research is needed to understand its impact on treatment outcomes.

DOI: https://doi.org/10.1080/01635581.2024.2382390
J Exp Clin Cancer Res. 2024 Jul 22. 43(1): 202

CXCL5 impedes CD8+ T cell immunity by upregulating PD-L1 expression in lung cancer via PXN/AKT signaling phosphorylation and neutrophil chemotaxis.

Dantong Sun, Lipin Tan, Yongbing Chen, Qiang Yuan, Kanqiu Jiang, Yangyang Liu, Yuhang Xue, Jinzhi Zhang, Xianbao Cao, Minzhao Xu, Yang Luo, Zhonghua Xu, Zhonghen Xu, Weihua Xu, Mingjing Shen.

   BACKGROUND: Lung cancer remains one of the most prevalent cancer types worldwide, with a high mortality rate. Upregulation of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) may represent a key mechanism for evading immune surveillance. Immune checkpoint blockade (ICB) antibodies against PD-1 or PD-L1 are therefore widely used to treat patients with lung cancer. However, the mechanisms by which lung cancer and neutrophils in the microenvironment sustain PD-L1 expression and impart stronger inhibition of CD8+ T cell function remain unclear.
METHODS: We investigated the role and underlying mechanism by which PD-L1+ lung cancer and PD-L1+ neutrophils impede the function of CD8+ T cells through magnetic bead cell sorting, quantitative real-time polymerase chain reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assays, confocal immunofluorescence, gene silencing, flow cytometry, etc. In vivo efficacy and safety studies were conducted using (Non-obeseDiabetes/severe combined immune deficiency) SCID/NOD mice. Additionally, we collected clinical and prognostic data from 208 patients who underwent curative lung cancer resection between 2017 and 2018.
RESULTS: We demonstrated that C-X-C motif chemokine ligand 5 (CXCL5) is markedly overexpressed in lung cancer cells and is positively correlated with a poor prognosis in patients with lung cancer. Mechanistically, CXCL5 activates the phosphorylation of the Paxillin/AKT signaling cascade, leading to upregulation of PD-L1 expression and the formation of a positive feedback loop. Moreover, CXCL5 attracts neutrophils, compromising CD8+ T cell-dependent antitumor immunity. These PD-L1+ neutrophils aggravate CD8+ T cell exhaustion following lung cancer domestication. Combined treatment with anti-CXCL5 and anti-PD-L1 antibodies significantly inhibits tumor growth in vivo.
CONCLUSIONS: Our findings collectively demonstrate that CXCL5 promotes immune escape through PD-L1 upregulation in lung cancer and neutrophils chemotaxis through autocrine and paracrine mechanisms. CXCL5 may serve as a potential therapeutic target in synergy with ICBs in lung cancer immunotherapy.

Keywords:  CXCL5; Neutrophils; PD-L1; PXN/AKT signaling; T cell immunity

DOI:  https://doi.org/10.1186/s13046-024-03122-8
Biomol Biomed. 2024 Jul 14.

Prognostic value of immunotherapy in advanced non-small cell lung cancer based on baseline and dynamic changes in hemoglobin, albumin, and platelets.

Hui Su, Chao Yu, Guiming Sun, Baozhong Wang, Yingjie Gao, Xiaolan Liu, Qingcui Song, Xuezhen Ma.

Immune checkpoint inhibitors enhance the tumor-killing ability of T-cells in non-small cell lung cancer (NSCLC), thereby boosting overall survival (OS) and transforming treatment for advanced stages. However, challenges persist, including low response rates and the absence of effective markers for candidate selection. This study evaluated the impact of hemoglobin, albumin, and platelet (HALP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on immunotherapy efficacy and survival in advanced NSCLC. Furthermore, the study aimed to develop a nomogram based on these parameters. Clinical and hematological data from patients diagnosed with NSCLC who received immunotherapy were analyzed. Efficacy was assessed using the immune Response Evaluation Criteria in Solid Tumors (iRECIST), and progression-free survival (PFS) and OS were analyzed. Prediction models were based on baseline and post-treatment HALP, NLR, and PLR. The 203 included patients had a median follow-up of 16 months, a median PFS (mPFS) of 7 months (6.0 - 8.0), while the median OS (mOS) was not available (24.0 - not available). The PLR before treatment (PLR0) was linked to a higher disease control rate (DCR) (odds ratio [OR] = 0.258), while initial immunotherapy and NLR after four cycles of treatment (NLR4C) significantly boosted the objective response rate (ORR). Cox regression showed that HALP before treatment (HALP0), HALP after four cycles of treatment (HALP4C), and NLR before treatment (NLR0) significantly influenced PFS. Additionally, HALP0, NLR0, and PLR after four cycles of treatment (PLR4C) were associated with OS. The C-indices for PFS and OS were 0.823 and 0.878, respectively, indicating good prediction accuracy. HALP, NLR, and PLR at various time points effectively predicted immunotherapy response in advanced NSCLC patients. Low HALP with high NLR and PLR indicated a poor prognosis. The findings can provide the basis for stratified randomized controlled trials (RCTs) in the future.

DOI: https://doi.org/10.17305/bb.2024.10833
Cancer Med. 2024 Jul;13(14): e70007

Comparison of treatment outcome between first-line combination immunotherapy (anti-PD-L1 or anti-PD1) with or without chemotherapy and chemotherapy alone in advanced non-small cell lung cancer patients in tertiary care hospital.

Danainut Naratornsirakul, Busyamas Chewaskulyong, Sarawut Kongkarnka, Songporn Oranratnachai.

   BACKGROUND: Despite promising outcomes of first-line immunotherapy with or without chemotherapy in advanced non-small cell lung cancer (NSCLC), limited accessibility due to reimbursement was remain the problem in low to middle income countries. This study aimed to evaluate real-world effectiveness of immunotherapy in patients with advanced NSCLC in Northern Thailand.
METHOD: A retrospective, single-centered cohort, was conducted. Patients with advanced NSCLC who underwent PD-L1 testing (excluding EGFR and ALK mutations) and were treated with immunotherapy or without chemotherapy or chemotherapy alone were included. The primary end point was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events.
RESULTS: A total of 123 patients, of which 21 patients received immunotherapy-based regimen and 102 patients received chemotherapy alone. The median PFS was 11.9 months in immunotherapy-based group compared to 5.93 months in the chemotherapy group, with a. hazard ratio (HR) of 0.4 (95% confidence interval [CI], 0.23 to 0.68; p = 0.001). Similarly, the median OS was 26.68 months in the immunotherapy-based group and 11.21 months in the chemotherapy group, with HR of 0.42 (95% CI 0.22-0.8; p = 0.009). ORRs were significantly higher in the immunotherapy-based group, with 65% of patients showing a response compared to 32% in the chemotherapy group (p = 0.006).
CONCLUSION: The result of this real-world study in patients with advanced stage NSCLC indicate that first-line immunotherapy-based regimen was associated with significantly greater PFS, OS, and ORR with a safety profile consistent with pivotal studies.

Keywords:  anti‐PD‐L1; anti‐Pd1 immunotherapy; immunotherapy; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/cam4.70007
J Surg Oncol. 2024 Jul 24.

Circulating levels of galectin-9 are a potential biomarker of survival in advanced non-small-cell lung cancer.

Guilherme Vieira de Mendonça Filho, Guilherme Jorge Costa, Mario R Martins, Leuridan C Torres.

   BACKGROUND: The immune system is recognized to have therapeutic potential to destroy cancer cells. Soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) and its ligand galectin 9 (Gal-9) cause suppression of cytokine production, cell cycle arrest and cell death. sTIM-3 and Gal-9 levels may have prognostic implications in non-small-cell lung cancer (NSCLC) patients.
METHODS: This prospective cohort study was performed at Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Pernambuco, Brazil. Fifty-eight patients were diagnosed with advanced NSCLC from January 2019 to January 2020.
RESULTS: The age median was of 64.0 years. Soluble galectin-9 (sGal-9) levels in the smokers compared to nonsmoker patients (p < 0.0001). By using the receiver operating characteristic curve, we found that a baseline of 1694 pg/mL (cutoff). sGAL9 with specificity (72.2%), sensitivity (83.2%) and area under the curve = 0.8497 (p < 0.0004). Until 18.2 months, 46.8% and 72.9% were alive in the sGAL9low and sGAL9high groups, respectively (log-rank test; p = 0.02). The median survival was 15.9 months for sGAL9low (≤1694 pg/mL).
CONCLUSION: This study indicated an association of tobacco with the release of circulating sGal-9 levels and the accuracy of sGal-9 as a potential biomarker predictive of survival time in advanced NSCLC patients. Furthermore, sGal-9 has may be a potential therapeutic target in the advanced NSCLC.

Keywords:  Gal‐9 levels; NSCLC; TIM‐3; biomarkers; smokers; survival

DOI:  https://doi.org/10.1002/jso.27758
Biochem Biophys Res Commun. 2024 Jul 23. pii: S0006-291X(24)00977-X. [Epub ahead of print]733 150441

The 3D organ-on-a-chip model unveils a dual role of GDF-15 in vascular growth.

Katarzyna Sarad, Józef Dulak, Agnieszka Jaźwa-Kusior.

  Pathological conditions such as oxidative stress or inflammation may alter the homeostasis of adventitia triggering vascular wall remodeling and abnormal angiogenesis, what can lead to development of atherosclerosis. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine and metabolic regulator, but its role in angiogenesis is not yet fully defined. Here we utilized an organ-on-a-chip technology to analyze endothelial sprouting in an adventitia-resembling microenvironment. We analyzed angiogenic responses to growth factor gradient across the extracellular matrix-resembling fibrin gel and in cell co-culture in response to GDF-15-treated adventitial fibroblasts. We observed that GDF-15 enhanced the pro-angiogenic effect of vascular endothelial growth factor. On the other hand, GDF-15-treated adventitial fibroblasts decreased endothelial sprouting. GDF-15 seems to indirectly affect endothelial cells and, depending on the microenvironment, its effect can be either pro- or anti-angiogenic.

Keywords:  Adventitia; Angiogenesis; Fibroblast; GDF-15; Organ-on-a-chip

DOI:  https://doi.org/10.1016/j.bbrc.2024.150441
Clin Exp Med. 2024 Jul 25. 24(1): 169

Deciphering the prognostic role of endoplasmic reticulum stress in lung adenocarcinoma: integrating prognostic prediction and immunotherapy strategies.

Bing Wen, Pengpeng Zhang, Jiping Xie, Zhaokai Zhou, Ge Zhang, Lianmin Zhang, Zhenfa Zhang.

  Endoplasmic reticulum stress (ERS) is a critical factor influencing lung adenocarcinoma (LUAD) progression and patient outcomes. In this study, we analyzed gene expression data from LUAD samples sourced from The Cancer Genomic Atlas and Gene Expression Omnibus databases. Utilizing advanced statistical methods including LASSO and Cox regression, we developed a ERS-associated signature (ERAS) based on ten ERS-related genes. This model stratified patients into high- and low-risk groups, with the high-risk group exhibiting decreased survival rates, elevated tumor mutational burden, and heightened chemotherapy sensitivity. Additionally, we observed lower immune and ESTIMATE scores in the high-ERAS group, indicating a potentially compromised immune response. Experimental validation through quantitative real-time polymerase chain reaction confirmed the utility of our model. Furthermore, we constructed a nomogram to predict 1-, 3-, and 5-year survival rates, providing clinicians with a valuable tool for personalized patient management. In conclusion, our study demonstrates the efficacy of the ERAS in identifying high-ERAS LUAD patients, offering promising implications for improved prognostication and treatment strategies.

Keywords:  Endoplasmic reticulum stress; Lung adenocarcinoma; Prognosis,signature; TME

DOI:  https://doi.org/10.1007/s10238-024-01439-4
Cell Death Dis. 2024 Jul 26. 15(7): 532

PPAR-γ/NF-kB/AQP3 axis in M2 macrophage orchestrates lung adenocarcinoma progression by upregulating IL-6.

Guofu Lin, Lanlan Lin, Xiaohui Chen, Luyang Chen, Jiansheng Yang, Yanling Chen, Danwen Qian, Yiming Zeng, Yuan Xu.

Aquaporin 3 (AQP3), which is mostly expressed in pulmonary epithelial cells, was linked to lung adenocarcinoma (LUAD). However, the underlying functions and mechanisms of AQP3 in the tumor microenvironment (TME) of LUAD have not been elucidated. Single-cell RNA sequencing (scRNA-seq) was used to study the composition, lineage, and functional states of TME-infiltrating immune cells and discover AQP3-expressing subpopulations in five LUAD patients. Then the identifications of its function on TME were examined in vitro and in vivo. AQP3 was associated with TNM stages and lymph node metastasis of LUAD patients. We classified inter- and intra-tumor diversity of LUAD into twelve subpopulations using scRNA-seq analyses. The analysis showed AQP3 was mainly enriched in subpopulations of M2 macrophages. Importantly, mechanistic investigations indicated that AQP3 promoted M2 macrophage polarization by the PPAR-γ/NF-κB axis, which affected tumor growth and migration via modulating IL-6 production. Mixed subcutaneous transplanted tumor mice and Aqp3 knockout mice models were further utilized, and revealed that AQP3 played a critical role in mediating M2 macrophage polarization, modulating glucose metabolism in tumors, and regulating both upstream and downstream pathways. Overall, our study demonstrated that AQP3 could regulate the proliferation, migration, and glycometabolism of tumor cells by modulating M2 macrophages polarization through the PPAR-γ/NF-κB axis and IL-6/IL-6R signaling pathway, providing new insight into the early detection and potential therapeutic target of LUAD.

DOI: https://doi.org/10.1038/s41419-024-06919-9