Rotem Leshem, Kieran Neil Sefton, Chun Wai Wong, I-Hsuan Lin, Dervla Tamara Isaac, Mario Niepel, Adam Hurlstone
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引用次数: 0
Abstract
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.
期刊介绍:
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.