A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis

Elife. 2021 Jun 11:10:e66222. doi: 10.7554/eLife.66222.

Abstract

Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.

Keywords: IL-18; IL-20; IL20RA; cancer biology; human; immune crosstalk; metastasis; mouse; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems*
  • Cell Line, Tumor
  • Epithelium / immunology
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Interleukins / genetics*
  • Interleukins / metabolism
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / genetics*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism
  • Peritoneal Cavity / pathology
  • Receptors, Interleukin / genetics*
  • Receptors, Interleukin / metabolism
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • Interleukins
  • Receptors, Interleukin
  • interleukin-20 receptor
  • interleukin-24
  • interleukin 20

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.