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DUX4 是转移性癌症中免疫逃逸和免疫治疗失败的常见驱动因素。

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.

机构信息

Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States.

Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States.

出版信息

Elife. 2024 Jun 3;12:RP89017. doi: 10.7554/eLife.89017.

DOI:10.7554/eLife.89017
PMID:38829686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11147511/
Abstract

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

摘要

癌症的免疫逃逸导致许多转移性癌症患者的检查点免疫疗法失败。最近，胚胎转录因子 DUX4 被描述为一种干扰素-γ信号和抗原呈递的抑制剂，它在一小部分原发性肿瘤中异常表达。在这里，我们报告说，表达是转移性肿瘤的一个共同特征，约 10-50%的晚期膀胱癌、乳腺癌、肾癌、前列腺癌和皮肤癌表达。表达与免疫细胞排斥和对 PD-L1 阻断的客观反应降低显著相关，在一个大型尿路上皮癌患者队列中。即使在该队列中考虑了肿瘤突变负担和其他分子及临床特征后，表达仍然是生存的显著预测因子，表达与中位生存时间缩短超过 1 年相关。我们的数据为未来开发 DUX4 作为检查点免疫治疗耐药的生物标志物和治疗靶点提供了动力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/cbab33fbea6f/elife-89017-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/0b92842437b4/elife-89017-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/43dc5d665512/elife-89017-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/bb26e420cf4f/elife-89017-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/1beff2629031/elife-89017-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/19af34cc89c9/elife-89017-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/628f829cf53a/elife-89017-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/64a9b644372b/elife-89017-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/c939c73a6c72/elife-89017-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/cbab33fbea6f/elife-89017-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/0b92842437b4/elife-89017-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/43dc5d665512/elife-89017-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/b43cd3da72ae/elife-89017-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/bb26e420cf4f/elife-89017-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/1beff2629031/elife-89017-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/19af34cc89c9/elife-89017-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/628f829cf53a/elife-89017-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/64a9b644372b/elife-89017-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/c939c73a6c72/elife-89017-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f11/11147511/cbab33fbea6f/elife-89017-fig5-figsupp1.jpg

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