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Single-Cell RNA Sequencing of Baseline PBMCs Predicts ICI efficacy and irAE Severity in NSCLC Patients

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285888 | GEO | 2025/05/19

REPOSITORIES: GEO

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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.

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Single-Cell RNA Sequencing of Baseline PBMCs Predicts ICI efficacy and irAE Severity in NSCLC Patients

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