Single-Cell RNA Sequencing of Baseline PBMCs Predicts ICI efficacy and irAE Severity in NSCLC Patients
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PROVIDER: PRJNA1206711 | ENA |
REPOSITORIES: ENA
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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: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:34 NSCLC cell lines were transcriptionally profiled against a reference mix of 45 NSCLC cell lines to look subtype specific differential gene expression 34 individual cell lines were compared to a reference mix consiting of 45 NSCLC cell lines
2013-01-18 | E-GEOD-43567 | biostudies-arrayexpress
Project description:34 NSCLC cell lines were transcriptionally profiled against a reference mix of 45 NSCLC cell lines to look subtype specific differential gene expression
2013-01-18 | GSE43567 | GEO
Project description:To investigate a non-invasive strategy for immune monitoring the peripheral blood by flow cytometry, to address the critical need to itdentify predictive immunological biomarkers that correlate with treatment response Peripheral blood mononuclear cells (PBMCs) from 19 non–small-cell lung cancer (NSCLC) patients before and after ICI treatment and four healthy human donors were evaluated, utilizing spectral flow to monitor 24 immune cell markers simultaneously over the course of treatment. We performed immune cell profiling analysis using data obtained from RNA-seq of 19 different patients before and after immunotherapy, to validate the multi-color flow based immune profiling
2023-08-03 | GSE235048 | GEO
Project description:<p><strong>OBJECTIVES:</strong> High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.</p><p><strong>MATERIALS AND METHODS:</strong> Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.</p><p><strong>RESULTS:</strong> In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).</p><p><strong>CONCLUSION: </strong>Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.</p>
2022-08-05 | MTBLS5267 | MetaboLights
Project description:PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) Cell Plasticity responsible for ICI-Resistance
| PRJNA1073841 | ENA
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: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:Mutation analysis of 77 frequently mutated genes in NSCLC in plasma DNA and corresponding PBMCs of NSCLC patients under ICI using the AVENIO Expanded Kit.
| EGAD00001007930 | EGA