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PBRM1 and the glycosylphosphatidylinositol biosynthetic pathway promote tumor killing mediated by MHC-unrestricted cytotoxic lymphocytes.

Authors
  • Menasche, Bridget L1
  • Davis, Eric M1
  • Wang, Shifeng1, 2
  • Ouyang, Yan1
  • Li, Suzhao3
  • Yu, Haijia1, 4
  • Shen, Jingshi5
  • 1 Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
  • 2 Department of Chinese Medicine Information Science, Beijing University of Chinese Medicine, Beijing 102488, China. , (China)
  • 3 Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 4 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China. , (China)
  • 5 Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA. [email protected]
Type
Published Article
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Nov 01, 2020
Volume
6
Issue
48
Identifiers
DOI: 10.1126/sciadv.abc3243
PMID: 33246952
Source
Medline
Language
English
License
Unknown

Abstract

Major histocompatibility complex (MHC)-unrestricted cytotoxic lymphocytes (CLs) such as natural killer (NK) cells can detect and destroy tumor and virus-infected cells resistant to T cell-mediated killing. Here, we performed genome-wide genetic screens to identify tumor-intrinsic genes regulating killing by MHC-unrestricted CLs. A group of genes identified in our screens encode enzymes for the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which is not involved in tumor response to T cell-mediated cytotoxicity. Another gene identified in the screens was PBRM1, which encodes a subunit of the PBAF form of the SWI/SNF chromatin-remodeling complex. PBRM1 mutations in tumor cells cause resistance to MHC-unrestricted killing, in contrast to their sensitizing effects on T cell-mediated killing. PBRM1 and the GPI biosynthetic pathway regulate the ligands of NK cell receptors in tumor cells and promote cytolytic granule secretion in CLs. The regulators identified in this work represent potential targets for cancer immunotherapy. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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