Abstract
Cancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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ADP-Ribosylation Factor 1 / genetics
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ADP-Ribosylation Factor 1 / metabolism*
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ADP-Ribosylation Factor 1 / pharmacology
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Alarmins
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Animals
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Antineoplastic Agents / immunology*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Dendritic Cells / immunology
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Endoplasmic Reticulum Stress / drug effects
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Female
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Gastrointestinal Neoplasms / metabolism
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Gastrointestinal Neoplasms / pathology
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Gastrointestinal Neoplasms / therapy
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Gene Knockdown Techniques
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Humans
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Lipid Metabolism / physiology*
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Lipolysis / drug effects
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms / therapy
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / drug effects
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Neoplastic Stem Cells / cytology
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism*
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T-Lymphocytes / immunology
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Tamoxifen / pharmacology
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Vaccination
Substances
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Alarmins
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Antineoplastic Agents
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Tamoxifen
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ADP-Ribosylation Factor 1