A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis.
A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis.
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系统性 CRISPR 筛选揭示了 IL-20/IL20RA 介导的免疫串扰可预防卵巢癌转移。
作者：
Li J;Qin X;Shi J;Wang X;Li T;Xu M;Chen X;Zhao Y;Han J;Piao Y;Zhang W;Qu P;Wang L;Xiang R;Shi Y
癌细胞在腹膜腔内的跨体腔扩散发生在大多数最初诊断的卵巢癌 (OC) 患者中，并且是大多数癌症相关死亡的原因。然而，OC 细胞如何与腹膜基质细胞相互作用以逃避免疫监视仍然很大程度上未被探索。在这里，通过体内全基因组 CRISPR/Cas9 筛选，我们发现 IL20RA 在 OC 患者腹膜转移期间急剧下降，是预防 OC 跨体腔转移的关键因素。在高度转移的 OC 细胞中重建 IL20RA 可以极大地抑制跨体腔转移。 OC细胞播散到腹膜腔后，会极大地诱导腹膜间皮细胞表达IL-20和IL-24，进而激活OC细胞内的IL20RA下游信号传导，产生成熟的IL-18，最终导致巨噬细胞极化为M1样亚型，从而清除癌细胞。因此，我们展示了 OC 和间皮细胞之间 IL-20/IL20RA 介导的串扰，支持抑制转移的免疫微环境。
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.