bims-meluca 2025-03-09 papers

J Immunother Cancer. 2025 Mar 06. pii: e010612. [Epub ahead of print]13(3):

Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6/Jak/Stat3 in PD-L1-high lung cancer.

Hyein Jeong, Jaemoon Koh, Sehui Kim, Jeemin Yim, Seung Geun Song, Hanbyeol Kim, Yingying Li, Soo Hyun Lee, Yeon Kyu Chung, Hongsoon Kim, Chul-Hwan Lee, Hye Young Kim, Bhumsuk Keam, Se-Hoon Lee, Doo Hyun Chung, Yoon Kyung Jeon.

BACKGROUND: Some patients with non-small-cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs) despite programmed death-ligand 1 (PD-L1) expression. To address the mechanism of ICI resistance in PD-L1-positive NSCLC, we investigated the role of tumor-cell-intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression.
METHODS: Cohorts of NSCLC patients treated with ICI and public datasets were analyzed. PD-L1-overexpressing and PD-L1-knockdown NSCLC cells were submitted to RNA-seq, in vitro analyses, chromatin immunoprecipitation-qPCR, CUT&Tag, and biochemical assays. Human myeloid-derived suppressor cells (MDSCs) sorted from peripheral blood mononuclear cells were co-cultured with NSCLC cells and then assessed for their immunosuppressive activity on T-cells. Mouse Lewis lung carcinoma (LLC) cells with PD-L1 overexpression or knockdown were subcutaneously injected into wild-type or PD-1-knockout C57BL/6 mice in the presence of IL-6 and/or PD-1 blockade.
RESULTS: In the ICI cohort with RNA-seq data, the IL-6/Jak/Stat3 pathway was enriched, and IL-6 expression was higher in patients with PD-L1-high NSCLCs who did not respond to ICIs. In another cohort, a higher baseline serum IL-6 level was associated with poor clinical outcomes after ICI therapy. IL-6 expression and the IL-6/Jak/Stat3 pathway were enhanced in PD-L1-high NSCLCs in the ICI cohorts and The Cancer Genome Atlas analysis. IL-6 expression correlated positively with tumor-infiltrating MDSCs in NSCLCs. In NSCLC cells, PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting protein tyrosine phosphatase 1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 in the transcription of several cytokines (IL-6, TGF-β, TNF-α, IL-1β) and chemokines. PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSCs in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing LLC tumors were infiltrated by increased MDSCs with high immunosuppressive function, increased Tregs, and decreased granzyme B+ or IFNγ+ CD8 T-cells. These responses were mediated by IL-6 secreted from PD-L1-overexpressing tumor cells. Combined blockade of PD-1 and IL-6 was effective in tumor control and decreased MDSCs while increasing granzyme B+ or IFNγ+ CD8 T-cells.
CONCLUSIONS: The tumor-cell-intrinsic function of PD-L1 drives immunosuppression and tumor progression through the PD-L1/Jak/Stat3/IL-6/MDSC axis. This pathway represents a potential therapeutic target to improve ICI efficacy in PD-L1-high NSCLC.

Keywords: Immune Checkpoint Inhibitor; Immunosuppression; JAK-STAT; Lung Cancer; Myeloid-Derived Suppressor Cells

DOI: https://doi.org/10.1136/jitc-2024-010612

Genes Genomics. 2025 Mar 07.

Lactate released by lung adenocarcinoma (LUAD) cells promotes M2 macrophage polarization via the GPR132/cAMP/PKA pathway.

Xiao Chen, Zhongzheng Zhang, Kangwu Wang.

BACKGROUND: Increasing evidence suggests that lactate is an essential compound in the tumor microenvironment, and especially for macrophage cells. However, the mechanism by which lactate affects macrophages remains unclear.
OBJECTIVE: This study investigated whether and how lactate affects macrophage polarization in lung adenocarcinoma (LUAD).
METHODS: Clinical samples of LUAD and paracancerous tissue were obtained for evaluation of lactate dehydrogenase A (LDHA) expression. LUAD cell lines and THP-1 induced macrophages were used in this study. Quantitative real-time PCR (QPCR), western blotting, and immunohistochemical (IHC) staining were performed to detect gene expression. Flow cytometry and ELISA assays were used to detect the levels of M1 macrophage and M2 macrophage biomarkers.
RESULTS: LDHA was highly expressed in the LUAD tissues. Culture medium supernatants derived from LUAD cells (CM) promoted macrophage M2 polarization, and lactate levels were elevated in the CM. Inhibition of LDHA in LUAD cells decreased lactate levels and suppressed M2 macrophage polarization. Moreover, overexpression of GPR132 in macrophages promoted, while GPR132 knockdown in macrophages suppressed M2 macrophage polarization and cAMP (Cyclic Adenosine 3',5'-Monophosphate)/PKA (Protein Kinase) pathway activation induced by lactate. The effect of GPR132 overexpression was reversed by a PKA inhibitor (H-89).
CONCLUSION: Collectively, our results confirmed that lactate released by LUAD cells promoted M2 macrophage polarization via the GPR132/cAMP/PKA pathway.

Keywords: GPR132; LDHA; Lactate; Lung adenocarcinoma (LUAD); Macrophage polarization

DOI: https://doi.org/10.1007/s13258-025-01622-1

Clin Cancer Res. 2025 Mar 07.

-----Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma.

PURPOSE: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes.
EXPERIMENTAL DESIGN: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms.
RESULTS: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis.
CONCLUSIONS: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2000

Redox Biol. 2025 Feb 25. pii: S2213-2317(25)00080-1. [Epub ahead of print]81 103567

Suppression of the LKB1-AMPK-SLC7A11-GSH signaling pathway sensitizes NSCLC to albumin-bound paclitaxel via oxidative stress.

Dade Rong, Liangliang Gao, Yiguan Chen, Xiang-Zheng Gao, Mingzhu Tang, Haimei Tang, Yuan Gao, Guang Lu, Zhi-Qiang Ling, Han-Ming Shen.

Albumin-bound paclitaxel (nab-PTX) is an important chemotherapeutic drug used for the treatment of advanced and metastatic non-small cell lung cancer (NSCLC). One critical issue in its clinical application is the development of resistance; thus, a deeper understanding of the mechanisms underlying the primary resistance to nab-PTX is expected to help to develop effective therapeutic strategies to overcome resistance. In this study, we made an unexpected discovery that NSCLC with wild-type (WT) Liver kinase B1 (LKB1), an important tumor suppressor and upstream kinase of AMP-activated protein kinase (AMPK), is more resistant to nab-PTX than NSCLC with mutant LKB1. Mechanistically, LKB1 status does not alter the intracellular concentration of nab-PTX or affect its canonical pharmacological action in promoting microtubule polymerization. Instead, we found that LKB1 mediates AMPK activation, leading to increased expression of SLC7A11, a key amino acid transporter and intracellular level of glutathione (GSH), which then attenuates the production of reactive oxygen species (ROS) and apoptotic cell death induced by nab-PTX. On the other hand, genetic or pharmacological inhibition of AMPK in LKB1-WT NSCLC reduces the expression of SLC7A11 and intracellular GSH, increases ROS level, and eventually promotes the apoptotic cell death induced by nab-PTX in vitro. Consistently, the combination of nab-PTX with an AMPK inhibitor exhibits a greater therapeutic efficacy in LKB1-WT NSCLC using xenograft models in vivo. Taken together, our data reveal a novel role of LKB1-AMPK-SLC7A11-GSH signaling pathway in the primary resistance to nab-PTX, and provide a therapeutic strategy for the treatment of LKB1-WT NSCLC by targeting the LKB1-AMPK-SLC7A11-GSH pathway.

Keywords: AMPK; Albumin-bound paclitaxel; LKB1; Non-small lung cancer; ROS; SLC7A11

DOI: https://doi.org/10.1016/j.redox.2025.103567

Lung. 2025 Mar 01. 203(1): 38

Toll-Like Receptor 4 and 8 are Overexpressed in Lung Biopsies of Human Non-small Cell Lung Carcinoma.

Silvia Ceccarelli, Viola Pasqua Marzolesi, Jacopo Vannucci, Guido Bellezza, Claudia Floridi, Giuseppe Nocentini, Luigi Cari, Giovanna Traina, Davide Petri, Francesco Puma, Carmela Conte.

PURPOSE: Lung cancer is the leading cause of cancer death worldwide which includes two main types of carcinoma distinguished in non-small cell lung cancer (NSCLC) involving epithelial cells, and small cell lung cancer (SCLC) affecting neuronal cells and hormone secreting cells. Studies have shown a causal link between inflammation/innate immunity and onset of NSCLC. The present study aimed to evaluate the expression of Toll-like receptors (TLRs) 4 and TLR8 in peripheral blood mononuclear cells (PBMC) and in lung tissues of patients with NSCLC, useful for future prognostic tools for NSCLC.
METHODS: Patients surgically treated for NSCLC with anatomical resections and patients with benign disease were enrolled. The expression levels of TLR4 and TLR8 were determined by real time PCR and by immunohistochemical analysis in PBMC and in lung tissues, respectively. A preliminary in silico analysis including 1194 arrays from healthy and cancer tissues were extracted by Genevestigator database. The association between TLRs gene expression and survival outcome was also investigated.
RESULTS: Bioinformatics analysis revealed that downregulation of TLR4 and TLR8 positively impacts the survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). However, no significant differences in TLR4 and TLR8 gene expression between case and control groups were observed in PBMC. A positive correlation was found in their expression levels. Interestingly, immunohistochemical analysis showed that the levels of TLR4 and TLR8 were higher in the lung tissues of patients with NSCLC than in the control group in terms of staining intensity and positive cells.
CONCLUSION: Albeit the precise role of TLRs is not fully defined, this study identified the potential involvement of TLR4 and TLR8 in the pathogenesis of NSCLC. Our data led us to hypothesize their potential role in overall survival which deserves to be explored further to establish whether TLR4 and TLR8 can represent positive prognostic indicators of disease in NSCLC.

Keywords: Inflammation; Non-small cell lung cancer; Toll-like receptors

DOI: https://doi.org/10.1007/s00408-025-00793-8