Abstract 976: The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis

Abstract Ovarian cancer has high mortality among all gynecological malignancies due to the lack of clear symptoms at early stage and the metastasis of cancer cells when diagnosed with advanced stage. The disseminated ovarian cancer cells have to overcome the immune surveillance in abdominal environment, which are rich in many types of immune cells, to survive and proliferate. However, the key genes and mechanisms preventing the metastasis of ovarian cancer cells into abdominal sites keep largely unexplored. Here, through an in vivo, genome-scale CRISPR/Cas9 knockout screening, we identified IL-20/IL24-IL20RA as a key checkpoint preventing the abdominal metastasis of ovarian cancer cells. In ovarian cancer patients, the level of IL20RA is dramatically decreased in metastatic cancer cells when compared with that in primary sites. Overexpression of IL20RA in highly metastatic ovarian cancer cells greatly suppressed the abdominal metastasis of ovarian cancer and the formation of ascites. In contrast, silencing IL20RA could increase the metastasis of ovarian cancer cells. We further examined IL20RA mediated crosstalk between the disseminated cancer cells and the immuno-microenvironment in mouse in vivo ovarian cancer models and in vitro co-culture experiments. Silencing IL20RA in ovarian cancer cells resulted in a dramatic decrease of M1 subtype of macrophages and increase of the M2 subtype of macrophages without affecting the population of T and B lymphocytes in ascites. Further mechanistic studies revealed that the ovarian cancer cells, when invaded into the abdominal sites, greatly induced the mesothelial cells in peritoneum to produce IL20RA ligands, i.e., IL-20 and IL-24, which in turn activated the IL20RA downstream signaling in ovarian cancer cells to trigger the production and maturation of IL-18. IL-18, when secreted into the microenvironment, was able to promote the polarization of macrophages into M1-subtype to clear the cancer cells. Thus, we identified a novel immune checkpoint IL-20/IL24-IL20RA that was always downregulated in metastatic ovarian cancer cells to prevent the formation of an anti-tumor immune microenvironment, which could be utilized to develop new strategies for the immunotherapy of ovarian cancers. Citation Format: Jia Li, Qin Xuan, JIE SHI, Longlong Wang, Yi Shi, Rong Xiang. The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 976.