Abstract
Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Basic-Leucine Zipper Transcription Factors / immunology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / radiation effects
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CTLA-4 Antigen / immunology
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Cell Line, Tumor
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Dendritic Cells / immunology*
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Dendritic Cells / radiation effects
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Exodeoxyribonucleases / metabolism*
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Exodeoxyribonucleases / radiation effects*
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Female
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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HEK293 Cells
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Humans
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Immunotherapy / methods
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Interferon-beta / metabolism
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Interferon-beta / radiation effects
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Mammary Neoplasms, Animal / genetics*
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Mammary Neoplasms, Animal / pathology
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Membrane Proteins / metabolism
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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, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Neoplasms / immunology*
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Neoplasms / radiotherapy*
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Nucleotidyltransferases / metabolism
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Phosphoproteins / metabolism*
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Phosphoproteins / radiation effects*
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / immunology
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Repressor Proteins / immunology
Substances
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Basic-Leucine Zipper Transcription Factors
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Ifnar1 protein, mouse
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Membrane Proteins
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Phosphoproteins
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Repressor Proteins
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SNFT protein, mouse
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STING1 protein, human
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Receptor, Interferon alpha-beta
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Interferon-beta
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Nucleotidyltransferases
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cGAS protein, human
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Exodeoxyribonucleases
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three prime repair exonuclease 1