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

Autor: Angelicola S; 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., Giunchi F; Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Ruzzi F; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Frascino M; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Pitzalis M; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Scalambra L; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Semprini MS; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Pittino OM; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Cappello C; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Siracusa I; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Chillico IC; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Di Noia M; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Turato C; Department of Molecular Medicine, University of Pavia, Pavia, Italy., De Siervi S; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Lescai F; Department of Biology and Biotechnology, University of Pavia, Pavia, Italy., Ciavattini T; Department of Biotechnology, University of Verona, Verona, Italy., Lopatriello G; Department of Biotechnology, University of Verona, Verona, Italy., Bertoli L; Department of Biotechnology, University of Verona, Verona, Italy., De Jonge H; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Iamele L; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Altimari A; Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Gruppioni E; Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy., Ardizzoni A; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy., Rossato M; Department of Biotechnology, University of Verona, Verona, Italy.; Genartis S.R.L., Verona, Italy., Gelsomino F; Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. francesco_gelsomino@aosp.bo.it., Lollini PL; Laboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.; IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy., Palladini A; Department of Molecular Medicine, University of Pavia, Pavia, Italy. arianna.palladini@unipv.it.; Unità Operativa di Oncologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. arianna.palladini@unipv.it.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2025 Jan 02; Vol. 23 (1), pp. 2. Date of Electronic Publication: 2025 Jan 02.
DOI: 10.1186/s12967-024-06023-8
Abstrakt: 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.
Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Human samples were collected after the patient gave her informed consent. The protocol was approved by the Ethics Committee Center Emilia-Romagna Region, Italy (GR-2018-12368031). Human samples and metadata including relevant clinical data were de-identified before being shared between laboratories involved in this study. All animal procedures were performed in accordance with European directive 2010/63/UE and Italian Law (No. DL26/2014). Experimental protocols were reviewed and approved by the institutional animal care and use committee of the University of Bologna and by the Italian Ministry of Health with letter 32/2020-PR. Consent for publication: Not applicable. Competing interests: Prof. Andrea Ardizzoni received research grants from Celgene, Bristol-Myers Squibb, Ipsen, and Roche; and honoraria for advisory roles from Bristol-Myers Squibb, Merck Sharp & Dohme, ROCHE, AstraZeneca, and Eli Lilly outside of the submitted work. Dr. Francesco Gelsomino received honoraria or personal fees for the advisory role or consulting from Eli Lilly, Novartis, AstraZeneca, Pfizer, Regeneron and Bristol-Myers Squibb outside the submitted work.
(© 2025. The Author(s).)
Databáze: MEDLINE
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