PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) Cell Plasticity responsible for ICI-Resistance
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ABSTRACT:
PROVIDER: PRJNA1073841 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27885846_1.fastq.gz | Fastqsanger.gz | |||
| SRR27885846_2.fastq.gz | Fastqsanger.gz | |||
| SRR27885847_1.fastq.gz | Fastqsanger.gz | |||
| SRR27885847_2.fastq.gz | Fastqsanger.gz | |||
| SRR27885848_1.fastq.gz | Fastqsanger.gz |
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Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have demonstrated outstanding clinical efficacy in the treatment of NSCLC patients, ICIs-based therapy has also been associated with a paradoxical acceleration of tumor growth defined as hyperprogressive disease (HPD). In this paper we evaluated distinct plasticity traits in a model of HPD-NSCLC, with the aim of clarifying the mechanisms contributing to ICI resistance that involve IFN-γ and PD-L1. For this purpose, primary cell cultures were established from two stage IV NSCLC samples obtained from a single patient: one, prior to ICI initiation (NSCLC-B, baseline) and the other at the time of radiological evidence of hyperprogression under ICI treatment (NSCLC-H, hyperprogression). Compared to NSCLC-B cells, NSCLC-H cells exhibited a more aggressive in vivo and in vitro behavior, higher MAPK activation and owned the ability to develop tumoroids. The 3500 differentially expressed transcripts, according to whole transcriptome analysis, well described the profound plastic evolution of cells from NSCLC-B to NSCLC-H culture, as well as the increase of CD44 in the NSCLC-H cell line model, in which transcripts of CD44 isoforms lacking the variant domain were abundant. Transcripts of genes involved in the cellular response to IFN-γ were down-modulated in NSCLC-H compared to NSCLC-B, together with CD274. Conversely, an up-regulation of genes related to inflammatory response, including IL1- and IFNGR1, was found. In vitro response to IFN- γ was compromised in both NSCLC-B and NSCLC-H cells, since IFN- γ failed to exert its antiproliferative effect on these cells and to effectively induce PD-L1 expression in 2D-growth assays. Nevertheless, the cytokine induced the activation of both type I and type II IFN-pathway mediators. In addition, treatment with IFN-γ induced NSCLC-H traits in NSCLC-B cells, promoting a striking increase in the number of NSCLC-B 3D-soft agar colonies. Low IFN-γ doses or modulation of PD-L1 contributed to the evolution of NSCLC-B towards NSCLC-H phenotype through the augment of CD44 on cell membrane, cell morphological changes and increased cell growth or sphere formation ability. In conclusion, we report a modulation of plasticity by PD-L1 modulation and IFN-γ in a NSCLC cell culture established from a treatment-naïve patient, who developed HPD under ICI therapy, suggesting an association between NSCLC plasticity and these main actors involved in ICI activity.
2024-12-31 | GSE255144 | GEO
Project description:BackgroundNon-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death worldwide. Although immune checkpoint inhibitors (ICIs) have shown remarkable clinical efficacy, they can also induce a paradoxical cancer acceleration, known as hyperprogressive disease (HPD), whose causative mechanisms are still unclear.MethodsThis study investigated the mechanisms of ICI resistance in an HPD-NSCLC model. Two primary cell cultures were established from samples of a NSCLC patient, before ICI initiation ("baseline", NSCLC-B) and during HPD ("hyperprogression", NSCLC-H). The cell lines were phenotypically and molecularly characterized through immunofluorescence, Western Blotting and RNA-Seq analysis. To assess cell plasticity and aggressiveness, cellular growth patterns were evaluated both in vitro and in vivo through 2D and 3D cell growth assays and patient-derived xenografts establishment. In vitro investigations, including the evaluation of cell sensitivity to interferon-gamma (IFN-γ) and cell response to PD-L1 modulation, were conducted to explore the influence of these factors on cell plasticity regulation.ResultsNSCLC-H exhibited increased expression of specific CD44 isoforms and a more aggressive phenotype, including organoid formation ability, compared to NSCLC-B. Plastic changes in NSCLC-H were well described by a deep transcriptome shift, that also affected IFN-γ-related genes, including PD-L1. IFN-γ-mediated cell growth inhibition was compromised in both 2D-cultured NSCLC-B and NSCLC-H cells. Further, the cytokine induced a partial activation of both type I and type II IFN-pathway mediators, together with a striking increase in NSCLC-B growth in 3D cell culture systems. Finally, low IFN-γ doses and PD-L1 modulation both promoted plastic changes in NSCLC-B, increasing CD44 expression and its ability to produce spheres.ConclusionsOur findings identified plasticity as a relevant hallmark of ICI-mediated HPD by demonstrating that ICIs can modulate the IFN-γ and PD-L1 pathways, driving tumor cell plasticity and fueling HPD development.
| S-EPMC11697469 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have revolutionized by offering remarkable clinical benefits and durable responses for patients with advanced non-small cell lung cancer (NSCLC). However, a very small percentage of patients responded to ICI treatment, and immune-related adverse events (irAEs) leading to treatment discontinuation remain challenges. Despite the recognized need for biomarkers that can predict both the efficacy of ICIs and the risk of irAEs, such biomarkers have yet to be clearly identified. In this study, we performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMC) from NSCLC patients prior to treatment with ICIs. We found that the immune response is generally reduced in patients with poor prognosis. However, the hypoxic environment is particularly more prominent in patients with primary resistance compared to those with acquired resistance. Meanwhile, granzyme and perforin are closely associated with favorable prognosis. We also identified IL1B and CXCL8 as key predictors of irAEs, with their activation linked to inflammation. Moreover, we found that PRF1 in CD8+ T cells and NK cells plays a critical mediator of complete responses and reduced irAE to ICI therapy. These findings deepen our understanding of the mechanisms of ICI efficacy and provide valuable information for optimizing immunotherapy strategies. By identifying biomarkers for both better prognosis and irAEs, this research lays the foundation for personalized immunotherapy approaches that aim to improve clinical outcomes while minimizing the risks associated with ICI treatment.
2025-05-19 | GSE285888 | GEO
Project description:Introduction: Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes. Methods: We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms. Results: In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1). Conclusion: Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.
2025-01-17 | GSE283829 | GEO
Project description:Single-Cell RNA Sequencing of Baseline PBMCs Predicts ICI efficacy and irAE Severity in NSCLC Patients
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Project description:MCF7 breast cancer cell lines: drug-resistant (OHT and ICI) cell lines vs. drug-sensitive (wild type) cell lines. Assessment of association between gene expression and methylation. Two comparisons: OHT-resistant vs. wild type, and ICI-resistant vs. wild type. OHT: 4-hydroxytamoxifen ICI: fulvestrant ((ICI 182780) This submission represents the methylation component of the study.
2011-10-04 | E-GEOD-25519 | biostudies-arrayexpress
Project description:Background: The tumor cell-intrinsic function of programmed cell death-ligand 1 (PD-L1) is poorly understood. The roles of the intrinsic function of PD-L1 in interleukin (IL)-6-mediated immunosuppression and the response to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) were investigated. 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, ChIP-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 no response to ICI in PD-L1-high NSCLCs. IL-6 expression in PD-L1-high NSCLCs correlated positively with MDSCs and Tregs, but negatively with cytotoxic lymphocytes. In another ICI cohort, a higher baseline serum IL-6 level was associated with poor clinical outcome after ICI therapy. PD-L1 activated Jak2/Stat3 signaling by binding to and inhibiting tyrosine phosphatase PTP1B. PD-L1 also bound to p-Stat3 in the nucleus, thus promoting the activity of p-Stat3 on the transcription of several cytokines (IL-6, TGFβ, TNFα, IL-1β) and chemokines (CXCL1, CXCL3, CXCL8). PD-L1-overexpressing NSCLC cells enhanced the migration and immunosuppressive activity of human MDSC in vitro, mediated by IL-6 and CXCL1. In both wild-type and PD-1-knockout mice, PD-L1-overexpressing mouse lung tumors were heavily infiltrated by MDSCs with high immunosuppressive function. Treg numbers were increased while the numbers of granzyme B+ or IFNγ+ CD8 T-cells decreased. These responses were shown to be 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 contributes to immunosuppression and tumor progression by MDSCs through the IL-6/Jak/Stat3 pathway, which may serve as therapeutic target to improve ICI efficacy in patients with PD-L1-high NSCLC.
2025-01-06 | GSE285029 | GEO
Project description:Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examined 6 cohorts within 25 ICI-induced SJS/TEN patients and conducted single-cell RNA sequencing (scRNA-seq) analysis, which revealed overexpression of macrophage-derived CXCL10 that recruited CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identified TNF signaling as the key pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identified that macrophage-eliciting CTL contribute the pathogenesis of ICI-induced epidermal necrolysis and provide the therapeutic targets for the management and prevention of SCAR induced by ICI therapy.
2024-08-26 | GSE273720 | GEO
Project description:MCF-7 breast cancer cells were treated with E2, ICI 182,789 (ICI), Raloxifene (Ral), and/or trans-hydroxytamoxifen (TOT) for 8 or 48 h. Duplicate samples are labeled set A or set B.
2007-09-27 | E-GEOD-848 | biostudies-arrayexpress
Project description:MCF7 breast cancer cell lines: drug-resistant (OHT and ICI) cell lines vs. drug-sensitive (wild type) cell lines. Assessment of association between gene expression and methylation.
2011-10-05 | GSE25519 | GEO