Cargando…
The unfolded protein response links tumor aneuploidy to local immune dysregulation
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 o...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647024/ https://www.ncbi.nlm.nih.gov/pubmed/34698427 http://dx.doi.org/10.15252/embr.202152509 |
_version_ | 1784610539041718272 |
---|---|
author | Xian, Su Dosset, Magalie Almanza, Gonzalo Searles, Stephen Sahani, Paras Waller, T Cameron Jepsen, Kristen Carter, Hannah Zanetti, Maurizio |
author_facet | Xian, Su Dosset, Magalie Almanza, Gonzalo Searles, Stephen Sahani, Paras Waller, T Cameron Jepsen, Kristen Carter, Hannah Zanetti, Maurizio |
author_sort | Xian, Su |
collection | PubMed |
description | 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 SCNA(low) and SCNA(high) 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. |
format | Online Article Text |
id | pubmed-8647024 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86470242021-12-20 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 EMBO Rep Articles 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 SCNA(low) and SCNA(high) 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. John Wiley and Sons Inc. 2021-10-26 2021-12-06 /pmc/articles/PMC8647024/ /pubmed/34698427 http://dx.doi.org/10.15252/embr.202152509 Text en © 2021 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Xian, Su Dosset, Magalie Almanza, Gonzalo Searles, Stephen Sahani, Paras Waller, T Cameron Jepsen, Kristen Carter, Hannah Zanetti, Maurizio The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title | The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title_full | The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title_fullStr | The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title_full_unstemmed | The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title_short | The unfolded protein response links tumor aneuploidy to local immune dysregulation |
title_sort | unfolded protein response links tumor aneuploidy to local immune dysregulation |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647024/ https://www.ncbi.nlm.nih.gov/pubmed/34698427 http://dx.doi.org/10.15252/embr.202152509 |
work_keys_str_mv | AT xiansu theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT dossetmagalie theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT almanzagonzalo theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT searlesstephen theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT sahaniparas theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT wallertcameron theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT jepsenkristen theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT carterhannah theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT zanettimaurizio theunfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT xiansu unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT dossetmagalie unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT almanzagonzalo unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT searlesstephen unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT sahaniparas unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT wallertcameron unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT jepsenkristen unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT carterhannah unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation AT zanettimaurizio unfoldedproteinresponselinkstumoraneuploidytolocalimmunedysregulation |