ArticlePloS one2019
Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Risk Factors of Immune-Mediated Hepatotoxicity Induced by Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis.Current oncology (Toronto, Ont.) · 2024Pooled it
- Macrophage-CD8medRxiv : the preprint server for health sciences · 2026Article
- Article
- Autoimmune Hepatitis Induced by Immune Checkpoint Inhibitors in Adults: A Systematic Review.Diagnostics (Basel, Switzerland) · 2026Review
- Heterogeneity of macrophages in PD-1/PD-L1 inhibitor therapy: a single-cell perspective.Cellular & molecular biology letters · 2026Review
- Ripk2 promotes CD8Cell death & disease · 2026Article
- Single-cell transcriptomics unveils the immunologic landscape of anti-PD-1-associated indirect drug-induced liver injury.Journal of gastroenterology · 2026Article
- Sex as a biological variable in nonclinical studies: Bridging scientific rigor, animal welfare, and regulatory expectations.Animal models and experimental medicine · 2026Review
- Circulating exhausted CD8+ effector memory cells differentiate immune checkpoint inhibitor-induced liver injury from other acute immune-mediated liver injuries.Journal for immunotherapy of cancer · 2026Article
- Human lncRNA, hLinfRNA7 (IDO1-AS) Regulates Cytokine Expression, Tryptophan Catabolism, and Inflammatory Response in Macrophage.Molecular and cellular biology · 2026Article
- Immune-mediated liver injury from checkpoint inhibitors: mechanisms, clinical characteristics and management.Nature reviews. Gastroenterology & hepatology · 2025Review
- Hepatotoxicity in Cancer Immunotherapy: Diagnosis, Management, and Future Perspectives.Cancers · 2024Review
- Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis.Journal for immunotherapy of cancer · 2024Article
- Gut microbiome for predicting immune checkpoint blockade-associated adverse events.Genome medicine · 2024Article
- Pathogenesis, pathological characteristics and individualized therapy for immune-related adverse effects.Chinese medical journal pulmonary and critical care medicine · 2023Review
- Effectiveness of tacrolimus in a case of immune checkpoint inhibitor-induced hepatotoxicity that was refractory to steroids and mycophenolate mofetil.Clinical journal of gastroenterology · 2023Article
- Stocking the toolbox-Using preclinical models to understand the development and treatment of immune checkpoint inhibitor-induced immune-related adverse events.Immunological reviews · 2023Review
- Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury.The Journal of allergy and clinical immunology · 2023Article
- A novel pathologic marker, indoleamine 2,3-dioxygenase 1, for the cholangiopathy of immune checkpoint inhibitors-induced immune mediated hepatotoxicity as adverse events and the prediction of additional ursodeoxycholic acid treatment.Medical molecular morphology · 2023Article
- A Review of the Pharmacokinetic Characteristics of Immune Checkpoint Inhibitors and Their Clinical Impact Factors.Pharmacogenomics and personalized medicine · 2023Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1-/- mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.