Pubblicazioni

Autori:

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

Titolo:

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

Anno:

2025

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Referee:

No

Nome rivista:

JOURNAL OF TRANSLATIONAL MEDICINE

ISSN Rivista:

1479-5876

N° Volume:

23

Numero o Fascicolo:

1

Intervallo pagine:

1-20

Parole chiave:

Hyperprogressive disease; IFN-γ; Immune checkpoint inhibitors; Non-Small Cell Lung Cancer; PD-L1; Tumor plasticity

Breve descrizione dei contenuti:

BackgroundNon-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.MethodsThis 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-gamma) and cell response to PD-L1 modulation, were conducted to explore the influence of these factors on cell plasticity regulation.ResultsNSCLC-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-gamma-related genes, including PD-L1. IFN-gamma-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-gamma doses and PD-L1 modulation both promoted plastic changes in NSCLC-B, increasing CD44 expression and its ability to produce spheres.ConclusionsOur findings identified plasticity as a relevant hallmark of ICI-mediated HPD by demonstrating that ICIs can modulate the IFN-gamma and PD-L1 pathways, driving tumor cell plasticity and fueling HPD development.

Id prodotto:

145893

Handle IRIS:

11562/1162595

ultima modifica:

20 maggio 2025

Citazione bibliografica:

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, PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) «JOURNAL OF TRANSLATIONAL MEDICINE» , vol. 23 , n. 1 , 2025 , pp. 1-20

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