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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Published in:Journal of translational medicine Vol. 23; no. 1; pp. 2 - 20
Main Authors: 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
Format: Journal Article
Language:English
Published: London BioMed Central 02.01.2025
BMC
Subjects:
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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Summary: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.
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ISSN:1479-5876
1479-5876
DOI:10.1186/s12967-024-06023-8