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

  1. Jia Li
  2. Xuan Qin
  3. Jie Shi
  4. Xiaoshuang Wang
  5. Tong Li
  6. Mengyao Xu
  7. Xiaosu Chen
  8. Yujia Zhao
  9. Jiahao Han
  10. Yongjun Piao
  11. Wenwen Zhang
  12. Pengpeng Qu
  13. Longlong Wang
  14. Rong Xiang
  15. Yi Shi

  • Curated by eLife

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    Evaluation Summary:

    The authors studied ovarian carcinoma and identified a potential role of interleukin 20 receptor subunit alpha (IL20RA) and of IL-20 in regulating the transcoelomic metastasis of ovarian carcinoma, where IL-20 signaling in tumors is protective. This leads to the production of IL-18 and an M1 macrophage phenotype, with reduction of metastasis. The study is of interest to investigators in the area of cancer and cytokines and has potential therapeutic ramifications.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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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.

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  1. Version published to 10.7554/elife.66222 on eLife
  2. eLife

    Reviewer #2 (Public Review):

    In the manuscript Li and colleagues explored the mechanisms that potentially regulated the transcoelomic metastasis of ovarian cancer. By using the in vivo genome-wide CRISPR/Cas9 screen in human SK-OV-3 cell line after transplanted in NOD-SCID mice, the authors identified that IL-20Ra was a potential protective factor preventing the transcoelomic metastasis of ovarian cancer. SK-OV-3 cells with higher expression of IL-20R have lower metastatic potential in vivo. On the contrary, a mouse cell line ID8 with lower IL20Ra expression metastasized aggressively, which could be reversed by over expressing IL-20Ra in the cells. In human, the metastasized ovarian cancers had lower expression of IL-20Ra than the primary tumors. Mechanistically, the authors hypothesized that IL-20 and IL-24 produced by peritoneum mesothelial could act on tumor cells through the IL-20Ra/IL-20Rb receptor to promote the production of IL-18. IL-18 could drive the macrophages into M1 like phenotypes, which in turn controlled the transcoelomic metastasis of the cancer. The in vivo phenotypes in this study were consistent with these hypotheses. The role of IL-20Ra in this setting is potentially interesting and novel.

  3. eLife

    Reviewer #1 (Public Review):

    The authors used a CRISPR screen to investigate the basis of metastasis of ovarian cancer (OC) cells. Overall, they identified two key genes, IL20RA, one of which was studied in detail. They identify an IL20/IL20RA communication between ovarian cancer cells and peritoneal mesothelial cells to promote M1 macrophages and prevent dissemination of the cancer cells. IL-20 mediated crosstalk is blocked in metastasized OC cells by decreased expression of IL-20RA. Interestingly, IL20RA is also decreased in cells from OC patients with peritoneal metastasis, and reconstitution of IL20RA in metastatic OC cells suppresses metastasis. Moreover, OC cells induce mesothelial cells to produce IL20 and IL24.

    Overall, this is a nice study. It is well-written, and the data are clear. A range of methodologies are used that support the conclusions, with both over-expression and under-expression related studies supporting some key conclusions.

    The overall model is that there is crosstalk between disseminated OC cells and mesothelial cells and macrophages. OC cells when disseminated into the peritoneal cavity stimulate mesothelial cells to produced IL20 and IL24, which via IL20RA trigger STAT3 to produced OAS/RNase L and production of IL-18, to promote an M1 phenotype. The M1 phenotype lowers metastasis. Highly metastatic cells block this pathway by decreasing IL20RA expression.

    These findings are interesting, with potential therapeutic ramifications.

  4. eLife

    Evaluation Summary:

    The authors studied ovarian carcinoma and identified a potential role of interleukin 20 receptor subunit alpha (IL20RA) and of IL-20 in regulating the transcoelomic metastasis of ovarian carcinoma, where IL-20 signaling in tumors is protective. This leads to the production of IL-18 and an M1 macrophage phenotype, with reduction of metastasis. The study is of interest to investigators in the area of cancer and cytokines and has potential therapeutic ramifications.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  5. Version published to 10.1101/2021.01.03.425154v1 on bioRxiv