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...

Full description

Saved in:
Bibliographic Details
Published in:EMBO reports 2021-12, Vol.22 (12), p.e52509-n/a
Main Authors: Xian, Su, Dosset, Magalie, Almanza, Gonzalo, Searles, Stephen, Sahani, Paras, Waller, T Cameron, Jepsen, Kristen, Carter, Hannah, Zanetti, Maurizio
Format: Article
Language:English
Subjects:
Aneuploidy
Arginase
Bone marrow
Cancer
Cell activation
Chromosome aberrations
Chromosomes
Copy number
Cytotoxicity
EMBO03
EMBO19
EMBO32
Gene expression
Genomes
Granzyme B
Humans
Immune system
Inflammation
Interferon
Links
Lymphocytes
Lymphocytes T
Macrophages
Neoplasms - genetics
Phenotypes
Protein folding
Proteins
Solid tumors
Splicing
T cells
Termination factors
Toxic diseases
Toxicity
Transcription
Tumor cells
tumor immune microenvironment
Tumor Microenvironment
Tumors
Unfolded Protein Response
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Synopsis Aneuploidy, the unfolded protein response (UPR) and dysregulated local immunity are a common feature of human solid tumors, however, the relationship between these three variables has not been explored before. This study shows that the UPR links aneuploidy in tumor cells to dysregulation of macrophages and T cells in the tumor microenvironment. A unique aneuploidy score (aneuploidy burden) was inversely correlated with T cell mediated cytotoxicity across 9,375 tumors from TCGA. As aneuploidy increases, there is a loss of coordination among the members of the unfolded protein response pathway. PERK and IRE1α (RIDD) branches of the UPR, but not ATF6, mediate the effects of aneuploidy on local immune cells in the TME. Aneuploid cells release factors that polarize human macrophages to a pro-inflammatory/immune suppressive phenotype and negatively regulate human T cells during activation. Graphical Abstract Aneuploidy, the unfolded protein response (UPR) and dysregulated local immunity are a common feature of human solid tumors, however, the relationship between these three variables has not been explored before. This study shows that the UPR links aneuploidy in tumor cells to dysregulation of macrophages and T cells in the tumor microenvironment.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202152509