ArticleJCI insight2017
Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity.
Article in JCI insight, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
28 citing papers in PubMed, 44 citations in OpenAlex.
- A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma.Nature medicine · 2020Trial
- Mechanism and intervention strategy of thymus atrophy in cancer immunotherapy.American journal of cancer research · 2026Review
- Activated STING in the thymic epithelium alters T cell development and selection leading to autoimmunity.The Journal of clinical investigation · 2025Article
- Endogenous thymic regeneration: restoring T cell production following injury.Nature reviews. Immunology · 2025Review
- Transcript splicing optimizes the thymic self-antigen repertoire to suppress autoimmunity.The Journal of clinical investigation · 2024Article
- Synergistic effect between denosumab and immune checkpoint inhibitors (ICI)? A retrospective study of 268 patients with ICI and bone metastases.Journal of bone oncology · 2024Article
- Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer.Cancer immunology research · 2024Article
- Repurposing drugs for solid tumor treatment: focus on immune checkpoint inhibitors.Cancer biology & medicine · 2023Review
- PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Bispecific Antibodies Progression in Malignant Melanoma.Frontiers in pharmacology · 2022Review
- Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium.Science immunology · 2021Article
- AIRE deficiency, from preclinical models to human APECED disease.Disease models & mechanisms · 2021Review
- Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy.Frontiers in immunology · 2021Review
- Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.Communications biology · 2020Article
- GILT in Thymic Epithelial Cells Facilitates Central CD4 T Cell Tolerance to a Tissue-Restricted, Melanoma-Associated Self-Antigen.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity - A Mini-Review.Frontiers in immunology · 2020Review
- Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology.Oncoimmunology · 2020Review
- The RANK-RANKL axis: an opportunity for drug repurposing in cancer?Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2019Review
- Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases.Cancer immunology, immunotherapy : CII · 2019Article
- Pulling RANK on Cancer: Blocking Aire-Mediated Central Tolerance to Enhance Immunotherapy.Cancer immunology research · 2019Review
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors. Thus, while protecting against autoimmunity, Aire also limits the generation of melanoma-reactive T cells. Here, we show that Aire deficiency in mice expands the pool of CD4+ T cells capable of melanoma cell eradication and has additive effects with anti-CTLA-4 antibody in slowing melanoma tumor growth and increasing survival. Moreover, pharmacologic blockade of central T cell tolerance and peripheral checkpoint blockade in combination enhanced antimelanoma immunity in a synergistic manner. In melanoma patients treated with anti-CTLA-4 antibody, clinical response to therapy was associated with a human Aire polymorphism. Together, these findings suggest that Aire-mediated central tolerance constrains the efficacy of peripheral checkpoint inhibition and point to simultaneous blockade of Aire and checkpoint inhibitors as a novel strategy to enhance antimelanoma immunity.
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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.