Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma
Background Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired res...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010683.full |
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| author | Chun Wai Wong Rotem Leshem Kieran Neil Sefton I-Hsuan Lin Dervla Tamara Isaac Mario Niepel Adam Hurlstone |
| author_facet | Chun Wai Wong Rotem Leshem Kieran Neil Sefton I-Hsuan Lin Dervla Tamara Isaac Mario Niepel Adam Hurlstone |
| author_sort | Chun Wai Wong |
| collection | DOAJ |
| description | Background Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance to ICI. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance. PARP14 inhibition prolongs PD-1 blockade responses in preclinical models, but fails to achieve full tumor clearance, suggesting the involvement of additional resistance mechanisms.Methods We identified a robust PARP14 catalytic inhibitor gene signature and evaluated its association with patient survival. Using preclinical models and single-cell RNA sequencing, we investigated immune and tumor cell adaptations to PARP14 inhibition combined with PD-1 blockade.Results Combining PARP14 inhibition and PD-1 blockade suppressed tumor-associated macrophages while increasing proinflammatory memory macrophages. Moreover, this combination mitigated the terminal exhaustion of cytotoxic T cells by inducing a quiescent state, thereby preserving functionality. Despite the enhanced immune responses, tumor cells developed adaptive resistance by engaging alternative immune evasion pathways.Conclusions Although adaptive resistance mechanisms re-emerge, PARP14 inhibition combined with PD-1 blockade offers a promising strategy to enhance treatment outcomes and overcome ICI resistance in melanoma, as immune cells are primed for further therapeutic interventions that leverage the quiescent state. |
| format | Article |
| id | doaj-art-5ac92f6d16ed48f0a08f6b66d4ba7fd8 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5ac92f6d16ed48f0a08f6b66d4ba7fd82025-01-28T12:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010683Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanomaChun Wai Wong0Rotem Leshem1Kieran Neil Sefton2I-Hsuan Lin3Dervla Tamara Isaac4Mario Niepel5Adam Hurlstone6Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UKDivision of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UKLydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, UKBioinformatics Core Facility, The University of Manchester, Manchester, UKRibon Therapeutics, Cambridge, Massachusetts, USARibon Therapeutics, Cambridge, Massachusetts, USADivision of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, UKBackground Programmed cell death 1 (PD-1) signaling blockade by immune checkpoint inhibitors (ICI) effectively restores immune surveillance to treat melanoma. However, chronic interferon-gamma (IFNγ)-induced immune homeostatic responses in melanoma cells contribute to immune evasion and acquired resistance to ICI. Poly ADP ribosyl polymerase 14 (PARP14), an IFNγ-responsive gene product, partially mediates IFNγ-driven resistance. PARP14 inhibition prolongs PD-1 blockade responses in preclinical models, but fails to achieve full tumor clearance, suggesting the involvement of additional resistance mechanisms.Methods We identified a robust PARP14 catalytic inhibitor gene signature and evaluated its association with patient survival. Using preclinical models and single-cell RNA sequencing, we investigated immune and tumor cell adaptations to PARP14 inhibition combined with PD-1 blockade.Results Combining PARP14 inhibition and PD-1 blockade suppressed tumor-associated macrophages while increasing proinflammatory memory macrophages. Moreover, this combination mitigated the terminal exhaustion of cytotoxic T cells by inducing a quiescent state, thereby preserving functionality. Despite the enhanced immune responses, tumor cells developed adaptive resistance by engaging alternative immune evasion pathways.Conclusions Although adaptive resistance mechanisms re-emerge, PARP14 inhibition combined with PD-1 blockade offers a promising strategy to enhance treatment outcomes and overcome ICI resistance in melanoma, as immune cells are primed for further therapeutic interventions that leverage the quiescent state.https://jitc.bmj.com/content/13/1/e010683.full |
| spellingShingle | Chun Wai Wong Rotem Leshem Kieran Neil Sefton I-Hsuan Lin Dervla Tamara Isaac Mario Niepel Adam Hurlstone Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma Journal for ImmunoTherapy of Cancer |
| title | Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma |
| title_full | Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma |
| title_fullStr | Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma |
| title_full_unstemmed | Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma |
| title_short | Combined PARP14 inhibition and PD-1 blockade promotes cytotoxic T cell quiescence and modulates macrophage polarization in relapsed melanoma |
| title_sort | combined parp14 inhibition and pd 1 blockade promotes cytotoxic t cell quiescence and modulates macrophage polarization in relapsed melanoma |
| url | https://jitc.bmj.com/content/13/1/e010683.full |
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