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

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 mechani...

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Vydáno v:	Journal of translational medicine Ročník 23; číslo 1; s. 2 - 20
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 02.01.2025 BMC
Témata:	Animals B7-H1 Antigen - metabolism Biomedical and Life Sciences Biomedicine Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Cell Plasticity - drug effects Cell Proliferation - drug effects Disease Progression Humans Hyperprogressive disease IFN-γ Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immune checkpoint inhibitors Interferon-gamma - metabolism Interferon-gamma - pharmacology Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Medicine/Public Health Mice Network Medicines Non-Small Cell Lung Cancer PD-L1 Tumor plasticity PD-L1 Hyperprogressive disease IFN-γ Non-Small Cell Lung Cancer Tumor plasticity Immune checkpoint inhibitors
ISSN:	1479-5876, 1479-5876
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1479-5876 1479-5876
DOI:	10.1186/s12967-024-06023-8