دورية أكاديمية
Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1.
| العنوان: | Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1. |
|---|---|
| المؤلفون: | Oreskovic E; Department of Genetics, Harvard Medical School, Boston, MA 02115.; HHMI, Harvard Medical School, Boston, MA 02115.; Division of Genetics, Brigham and Women's Hospital, Program in Virology, Harvard Medical School, Boston, MA 02115., Wheeler EC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Mengwasser KE; Department of Genetics, Harvard Medical School, Boston, MA 02115.; HHMI, Harvard Medical School, Boston, MA 02115.; Division of Genetics, Brigham and Women's Hospital, Program in Virology, Harvard Medical School, Boston, MA 02115., Fujimura E; Department of Genetics, Harvard Medical School, Boston, MA 02115.; HHMI, Harvard Medical School, Boston, MA 02115.; Division of Genetics, Brigham and Women's Hospital, Program in Virology, Harvard Medical School, Boston, MA 02115.; Chemical Biology Program, Harvard University, Cambridge, MA 02138., Martin TD; Department of Genetics, Harvard Medical School, Boston, MA 02115.; HHMI, Harvard Medical School, Boston, MA 02115.; Division of Genetics, Brigham and Women's Hospital, Program in Virology, Harvard Medical School, Boston, MA 02115., Tothova Z; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; zuzana_tothova@dfci.harvard.edu selledge@genetics.med.harvard.edu.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Elledge SJ; Department of Genetics, Harvard Medical School, Boston, MA 02115; zuzana_tothova@dfci.harvard.edu selledge@genetics.med.harvard.edu.; HHMI, Harvard Medical School, Boston, MA 02115.; Division of Genetics, Brigham and Women's Hospital, Program in Virology, Harvard Medical School, Boston, MA 02115. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Feb 15; Vol. 119 (7). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | B7-H1 Antigen/*metabolism , CCCTC-Binding Factor/*metabolism , Cell Cycle Proteins/*metabolism , Chromosomal Proteins, Non-Histone/*metabolism , Gene Expression Regulation, Neoplastic/*physiology , Neoplasms/*metabolism, B7-H1 Antigen/genetics ; CCCTC-Binding Factor/genetics ; Cell Cycle Proteins/genetics ; Cell Line ; Chromosomal Proteins, Non-Histone/genetics ; Humans ; Janus Kinases/genetics ; Janus Kinases/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Up-Regulation ; Cohesins |
| مستخلص: | 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. Competing Interests: Competing interest statement: S.J.E. is a cofounder of TSCAN Therapeutics, MAZE Therapeutics, and ImmuneID; serves on the Scientific Advisory Board of the above entities and Homology Medicines, Inc.; and is an advisor for MPM Capital. Z.T. receives research funding from Novartis. None of these interests in any way are connected to this study. (Copyright © 2022 the Author(s). Published by PNAS.) |
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| معلومات مُعتمدة: | F32 HL159905 United States HL NHLBI NIH HHS; K08 HL140138 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: CRISPR; PD-L1; cancer; cohesin |
| المشرفين على المادة: | 0 (B7-H1 Antigen) 0 (CCCTC-Binding Factor) 0 (CD274 protein, human) 0 (CTCF protein, human) 0 (Cell Cycle Proteins) 0 (Chromosomal Proteins, Non-Histone) 0 (NF-kappa B) 0 (STAG2 protein, human) 0 (STAT Transcription Factors) EC 2.7.10.2 (Janus Kinases) |
| تواريخ الأحداث: | Date Created: 20220212 Date Completed: 20220310 Latest Revision: 20231213 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC8851563 |
| DOI: | 10.1073/pnas.2120540119 |
| PMID: | 35149558 |
| قاعدة البيانات: | MEDLINE |
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