The unfolded protein response links tumor aneuploidy to local immune dysregulation.
The unfolded protein response links tumor aneuploidy to local immune dysregulation.
复制标题
未折叠的蛋白质反应将肿瘤非整倍性与局部免疫失调联系起来。
DOI：
10.15252/embr.202152509
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发表时间：
2021-12-06
期刊：
影响因子：
7.7
通讯作者：
Zanetti M
中科院分区：
文献类型：
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作者：
Xian S;Dosset M;Almanza G;Searles S;Sahani P;Waller TC;Jepsen K;Carter H;Zanetti M
在许多癌症类型中，非整倍体是一种与预后不良相关的染色体异常。在这里，我们测试了未折叠蛋白反应（UPR）在机制上将非整倍体和局部免疫失调联系起来的假设。使用单个体细胞拷贝数改变（SCNA）评分，包括全染色体、染色体臂和局灶性改变，在癌症基因组图谱（TCGA）数据库中对9375个样本进行泛癌分析，我们发现细胞毒性（CYT）评分与疾病分期呈负相关。在SCNAlow和SCNAhigh组中，UPR基因的共表达模式发生了显著变化。通路活性评分显示，在非整倍性的反应中，UPR的多个分支的活性增加。PERK分支显示出与CYT分数降低的最强关联。非整倍体细胞的条件培养基传递XBP1剪接，引起受体骨髓源性巨噬细胞IL - 6和精氨酸酶1的转录，并显著降低活化的人T细胞中IFN - γ和颗粒酶B的产生。我们提出UPR是肿瘤微环境中非整倍体和免疫失调之间的机制联系。非整倍体、未折叠蛋白反应（UPR）和局部免疫失调是人类实体肿瘤的共同特征，然而，这三个变量之间的关系尚未被探索。本研究表明，UPR将肿瘤细胞的非整倍体与肿瘤微环境中巨噬细胞和T细胞的失调联系起来。
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. 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.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.5
作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
64.8
作者：
通讯作者：
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