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The unfolded protein response links tumor aneuploidy to local immune dysregulation.
Xian, Su; Dosset, Magalie; Almanza, Gonzalo; Searles, Stephen; Sahani, Paras; Waller, T Cameron; Jepsen, Kristen; Carter, Hannah; Zanetti, Maurizio.
Afiliación
  • Xian S; Division of Medical Genetics Biostatistics, Department of Medicine, Bioinformatics and System Biology Program, University of California, San Diego, La Jolla, CA, USA.
  • Dosset M; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • Almanza G; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • Searles S; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • Sahani P; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • Waller TC; Division of Medical Genetics Biostatistics, Department of Medicine, Bioinformatics and System Biology Program, University of California, San Diego, La Jolla, CA, USA.
  • Jepsen K; IGM Genomics Center, University of California, San Diego, La Jolla, CA, USA.
  • Carter H; Division of Medical Genetics Biostatistics, Department of Medicine, Bioinformatics and System Biology Program, University of California, San Diego, La Jolla, CA, USA.
  • Zanetti M; The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
EMBO Rep ; 22(12): e52509, 2021 12 06.
Article en En | MEDLINE | ID: mdl-34698427
ABSTRACT
Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Respuesta de Proteína Desplegada / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Respuesta de Proteína Desplegada / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos