Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1

Proc Natl Acad Sci U S A. 2022 Feb 15;119(7):e2120540119. doi: 10.1073/pnas.2120540119.

Abstract

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.

Keywords: CRISPR; PD-L1; cancer; cohesin.

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • CCCTC-Binding Factor / genetics
  • CCCTC-Binding Factor / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms / metabolism*
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Up-Regulation

Substances

  • B7-H1 Antigen
  • CCCTC-Binding Factor
  • CD274 protein, human
  • CTCF protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • NF-kappa B
  • STAG2 protein, human
  • STAT Transcription Factors
  • cohesins
  • Janus Kinases