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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Vanpouille-Box, Claire ; Alard, Amandine ; Aryankalayil, Molykutty J ; Sarfraz, Yasmeen ; Diamond, Julie M ; Schneider, Robert J ; Inghirami, Giorgio ; Coleman, C Norman ; Formenti, Silvia C ; Demaria, Sandra

Nature communications, 2017-06, Vol.8 (1), p.15618-15618, Article 15618 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
Autor: Vanpouille-Box, Claire ; Alard, Amandine ; Aryankalayil, Molykutty J ; Sarfraz, Yasmeen ; Diamond, Julie M ; Schneider, Robert J ; Inghirami, Giorgio ; Coleman, C Norman ; Formenti, Silvia C ; Demaria, Sandra
Assuntos: Animals ; Basic-Leucine Zipper Transcription Factors - immunology ; Cancer research ; Cancer therapies ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - radiation effects ; Cell Line, Tumor ; CTLA-4 Antigen - immunology ; Dendritic cells ; Dendritic Cells - immunology ; Dendritic Cells - radiation effects ; Drug dosages ; Exodeoxyribonucleases - metabolism ; Exodeoxyribonucleases - radiation effects ; Female ; Fractionation ; Gene Expression Regulation - genetics ; Gene Expression Regulation - immunology ; Genes ; HEK293 Cells ; Humans ; Immunotherapy ; Immunotherapy - methods ; Interferon ; Interferon-beta - metabolism ; Interferon-beta - radiation effects ; Lymphocytes ; Mammary Neoplasms, Animal - genetics ; Mammary Neoplasms, Animal - pathology ; Medical research ; Medicine ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Neoplasms - immunology ; Neoplasms - radiotherapy ; Nucleotidyltransferases - metabolism ; Oncology ; Phosphoproteins - metabolism ; Phosphoproteins - radiation effects ; Radiation therapy ; Receptor, Interferon alpha-beta - genetics ; Receptor, Interferon alpha-beta - immunology ; Repressor Proteins - immunology ; Tumors
É parte de: Nature communications, 2017-06, Vol.8 (1), p.15618-15618, Article 15618
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Vanpouille-Box, Claire ; Alard, Amandine ; Aryankalayil, Molykutty J ; Sarfraz, Yasmeen ; Diamond, Julie M ; Schneider, Robert J ; Inghirami, Giorgio ; Coleman, C Norman ; Formenti, Silvia C ; Demaria, Sandra

England: Nature Publishing Group

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