PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD)
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 causativ...
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2025-01-01
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| author | Stefania Angelicola Francesca Giunchi Francesca Ruzzi Mariateresa Frascino Mary Pitzalis Laura Scalambra Maria Sofia Semprini Olga Maria Pittino Chiara Cappello Irene Siracusa Ilaria Candida Chillico Martina Di Noia Cristian Turato Silvia De Siervi Francesco Lescai Teresa Ciavattini Giulia Lopatriello Luca Bertoli Hugo De Jonge Luisa Iamele Annalisa Altimari Elisa Gruppioni Andrea Ardizzoni Marzia Rossato Francesco Gelsomino Pier-Luigi Lollini Arianna Palladini |
| author_facet | Stefania Angelicola Francesca Giunchi Francesca Ruzzi Mariateresa Frascino Mary Pitzalis Laura Scalambra Maria Sofia Semprini Olga Maria Pittino Chiara Cappello Irene Siracusa Ilaria Candida Chillico Martina Di Noia Cristian Turato Silvia De Siervi Francesco Lescai Teresa Ciavattini Giulia Lopatriello Luca Bertoli Hugo De Jonge Luisa Iamele Annalisa Altimari Elisa Gruppioni Andrea Ardizzoni Marzia Rossato Francesco Gelsomino Pier-Luigi Lollini Arianna Palladini |
| author_sort | Stefania Angelicola |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8064555d05ab4263a55859433e77db7d |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-8064555d05ab4263a55859433e77db7d2025-01-05T12:44:33ZengBMCJournal of Translational Medicine1479-58762025-01-0123112010.1186/s12967-024-06023-8PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD)Stefania Angelicola0Francesca Giunchi1Francesca Ruzzi2Mariateresa Frascino3Mary Pitzalis4Laura Scalambra5Maria Sofia Semprini6Olga Maria Pittino7Chiara Cappello8Irene Siracusa9Ilaria Candida Chillico10Martina Di Noia11Cristian Turato12Silvia De Siervi13Francesco Lescai14Teresa Ciavattini15Giulia Lopatriello16Luca Bertoli17Hugo De Jonge18Luisa Iamele19Annalisa Altimari20Elisa Gruppioni21Andrea Ardizzoni22Marzia Rossato23Francesco Gelsomino24Pier-Luigi Lollini25Arianna Palladini26Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di BolognaPathology Unit, IRCCS Azienda Ospedaliero-Universitaria di BolognaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaDepartment of Biology and Biotechnology, University of PaviaDepartment of Biotechnology, University of VeronaDepartment of Biotechnology, University of VeronaDepartment of Biotechnology, University of VeronaDepartment of Molecular Medicine, University of PaviaDepartment of Molecular Medicine, University of PaviaSolid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di BolognaSolid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di BolognaMedical Oncology, IRCCS Azienda Ospedaliero-Universitaria di BolognaDepartment of Biotechnology, University of VeronaMedical Oncology, IRCCS Azienda Ospedaliero-Universitaria di BolognaLaboratory of Immunology and Biology of Metastasis, Department of Medical and Surgical Sciences (DIMEC), University of BolognaDepartment of Molecular Medicine, University of PaviaAbstract 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.https://doi.org/10.1186/s12967-024-06023-8Non-Small Cell Lung CancerImmune checkpoint inhibitorsTumor plasticityHyperprogressive diseaseIFN-γPD-L1 |
| spellingShingle | Stefania Angelicola Francesca Giunchi Francesca Ruzzi Mariateresa Frascino Mary Pitzalis Laura Scalambra Maria Sofia Semprini Olga Maria Pittino Chiara Cappello Irene Siracusa Ilaria Candida Chillico Martina Di Noia Cristian Turato Silvia De Siervi Francesco Lescai Teresa Ciavattini Giulia Lopatriello Luca Bertoli Hugo De Jonge Luisa Iamele Annalisa Altimari Elisa Gruppioni Andrea Ardizzoni Marzia Rossato Francesco Gelsomino Pier-Luigi Lollini Arianna Palladini 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 Non-Small Cell Lung Cancer Immune checkpoint inhibitors Tumor plasticity Hyperprogressive disease IFN-γ PD-L1 |
| title | PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) |
| title_full | PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) |
| title_fullStr | PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) |
| title_full_unstemmed | PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) |
| title_short | PD-L1 and IFN-γ modulate Non-Small Cell Lung Cancer (NSCLC) cell plasticity associated to immune checkpoint inhibitor (ICI)-mediated hyperprogressive disease (HPD) |
| title_sort | pd l1 and ifn γ modulate non small cell lung cancer nsclc cell plasticity associated to immune checkpoint inhibitor ici mediated hyperprogressive disease hpd |
| topic | Non-Small Cell Lung Cancer Immune checkpoint inhibitors Tumor plasticity Hyperprogressive disease IFN-γ PD-L1 |
| url | https://doi.org/10.1186/s12967-024-06023-8 |
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