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程序性死亡受体配体1（PD-L1）和γ干扰素（IFN-γ）调节与免疫检查点抑制剂（ICI）介导的超进展性疾病（HPD）相关的非小细胞肺癌（NSCLC）细胞可塑性。

PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD).

作者信息

Angelicola Stefania, Giunchi Francesca, Ruzzi Francesca, Frascino Mariateresa, Pitzalis Mary, Scalambra Laura, Semprini Maria Sofia, Pittino Olga Maria, Cappello Chiara, Siracusa Irene, Chillico Ilaria Candida, Di Noia Martina, Turato Cristian, De Siervi Silvia, Lescai Francesco, Ciavattini Teresa, Lopatriello Giulia, Bertoli Luca, De Jonge Hugo, Iamele Luisa, Altimari Annalisa, Gruppioni Elisa, Ardizzoni Andrea, Rossato Marzia, Gelsomino Francesco, Lollini Pier-Luigi, Palladini Arianna

机构信息

Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.

出版信息

J Transl Med. 2025 Jan 2;23(1):2. doi: 10.1186/s12967-024-06023-8.

DOI:10.1186/s12967-024-06023-8

PMID:39748404

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11697469/

Abstract

BACKGROUND

Non-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.

METHODS

This 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.

RESULTS

NSCLC-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.

CONCLUSIONS

Our 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.

摘要

背景

非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因。尽管免疫检查点抑制剂（ICI）已显示出显著的临床疗效，但它们也可诱发一种矛盾的癌症加速现象，即超进展性疾病（HPD），其致病机制仍不清楚。

方法

本研究在HPD-NSCLC模型中研究ICI耐药的机制。从一名NSCLC患者的样本中建立了两种原代细胞培养物，一种在ICI治疗开始前（“基线”，NSCLC-B），另一种在HPD期间（“超进展”，NSCLC-H）。通过免疫荧光、蛋白质免疫印迹和RNA测序分析对细胞系进行表型和分子特征分析。为了评估细胞可塑性和侵袭性，通过二维和三维细胞生长试验以及患者来源的异种移植模型在体外和体内评估细胞生长模式。进行了体外研究，包括评估细胞对干扰素-γ（IFN-γ）的敏感性以及细胞对PD-L1调节的反应，以探讨这些因素对细胞可塑性调节的影响。

结果

与NSCLC-B相比，NSCLC-H表现出特定CD44异构体的表达增加以及更具侵袭性的表型，包括类器官形成能力。NSCLC-H中的可塑性变化通过深度转录组转移得到了很好的描述，这也影响了与IFN-γ相关的基因，包括PD-L1。在二维培养的NSCLC-B和NSCLC-H细胞中，IFN-γ介导的细胞生长抑制均受到损害。此外，细胞因子在三维细胞培养系统中诱导了I型和II型IFN途径介质的部分激活，同时NSCLC-B的生长显著增加。最后，低剂量IFN-γ和PD-L1调节均促进了NSCLC-B中的可塑性变化，增加了CD44表达及其产生球体的能力。