Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1.
Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1.
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DOI：
10.1073/pnas.2120540119
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发表时间：
2022-02-15
影响因子：
11.1
通讯作者：
Elledge SJ
中科院分区：
文献类型：
--
作者：
Oreskovic E;Wheeler EC;Mengwasser KE;Fujimura E;Martin TD;Tothova Z;Elledge SJ
PD-1/PD-L1免疫抑制轴在癌细胞的免疫逃避中起关键作用，靶向PD-1/PD-L1的疗法在某些癌症类型中显示出高疗效。了解癌症驱动因素如何调节免疫监视将有助于开发针对癌症介导的免疫逃避的新型治疗策略，并鉴定新的反应生物标志物。在这里，我们利用500个肿瘤抑制基因的精选文库进行遗传筛选，以确定PD-L1最重要的抑制因子中的粘附素亚基和CTCF。我们报告了额外的关键免疫调节分子PD-L2和MHC-I的上调，并描述了STAG 2粘附素亚基丢失的转录后果，包括诱导IFN和NF-κB反应，这对粘附素缺陷肿瘤的生物学和治疗有影响。免疫逃避是肿瘤演变的重要因素，而免疫抑制轴PD-1/PD-L1是逃避肿瘤免疫监视的常见机制。为了鉴定参与免疫逃避的癌症驱动因素，我们对调节PD-L1的基础和干扰素（IFN）诱导的细胞表面水平的肿瘤抑制基因进行了CRISPR-Cas9筛选。鉴定了PD-L1的多种调节剂，包括IRF 2、ARID 2、KMT 2D和AAMP。我们还鉴定了CTCF和粘附素复合物蛋白，它们是已知的染色质结构和转录的调节剂，是PD-L1细胞表面表达的最有效的负调节剂。此外，研究表明，粘附素亚基RAD 21的缺失上调PD-L2和MHC-I表面表达。粘附素对PD-L1和MHC-I的抑制在乳腺上皮细胞和骨髓细胞中是保守的。对STAG 2缺陷在上皮细胞和髓样细胞中的转录作用的全面检查揭示了强IFN和NF-κB表达特征的激活。JAK-STAT或NF-κB通路的抑制并没有导致RAD 21缺陷细胞中PD-L1上调的拯救，这表明更复杂或组合的机制在起作用。粘附素突变细胞中PD-L1和IFN上调的发现扩展了我们对粘附素缺陷细胞生物学以及PD-L1分子分子调节的理解。
The PD-1/PD-L1 immunoinhibitory axis plays a key role in immune evasion of cancer cells, and therapies targeting PD-1/PD-L1 show high efficacy in certain cancer types. Understanding how cancer drivers regulate immune surveillance will enable development of novel therapeutic strategies targeting cancer-mediated immune evasion, and identification of new biomarkers of response. Here, we utilized genetic screening with a curated library of 500 tumor suppressor genes to identify cohesin subunits and CTCF among the most significant suppressors of PD-L1. We report upregulation of additional key immune-regulatory molecules PD-L2 and MHC-I, and describe transcriptional consequences of loss of the STAG2 cohesin subunit, including an induction of IFN and NF-κB responses, which have implications for biology and treatment of cohesin-deficient tumors. Immune evasion is a significant contributor to tumor evolution, and the immunoinhibitory axis PD-1/PD-L1 is a frequent mechanism employed to escape tumor immune surveillance. To identify cancer drivers involved in immune evasion, we performed a CRISPR-Cas9 screen of tumor suppressor genes regulating the basal and interferon (IFN)-inducible cell surface levels of PD-L1. Multiple regulators of PD-L1 were identified, including IRF2, ARID2, KMT2D, and AAMP. We also identified CTCF and the cohesin complex proteins, known regulators of chromatin architecture and transcription, among the most potent negative regulators of PD-L1 cell surface expression. Additionally, loss of the cohesin subunit RAD21 was shown to up-regulate PD-L2 and MHC-I surface expression. PD-L1 and MHC-I suppression by cohesin were shown to be conserved in mammary epithelial and myeloid cells. Comprehensive examination of the transcriptional effect of STAG2 deficiency in epithelial and myeloid cells revealed an activation of strong IFN and NF-κB expression signatures. Inhibition of JAK-STAT or NF-κB pathways did not result in rescue of PD-L1 up-regulation in RAD21-deficient cells, suggesting more complex or combinatorial mechanisms at play. Discovery of the PD-L1 and IFN up-regulation in cohesin-mutant cells expands our understanding of the biology of cohesin-deficient cells as well as molecular regulation of the PD-L1 molecule.
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影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
3.5
作者：
Lee, SJ;Jang, BC;Choi, IH
通讯作者：
Choi, IH
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
64.5
作者：
Koren I;Timms RT;Kula T;Xu Q;Li MZ;Elledge SJ
通讯作者：
Elledge SJ