Role of the CXCR3 chemokine receptor in the tumor progression of ovarian cancer

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The CXCR3 chemokine receptor is expressed by tumorsuppressive lymphocytes and mediates their infiltration into solid cancers. Correspondingly, overexpression of the CXCR3 ligands CXCL9 and CXCL10 is associated with enhanced immune infiltration and prolonged survival in ovarian cancer. However, the tumor cells themselves can also overexpress CXCR3 which correlates with a worse prognosis. Therefore, besides en-hancing the immune infiltration an induction of CXCL9 and CXCL10 in the tumor microenvironment might also stimulate unwanted effects in the tumor cells. Therefore, elucidating the functional role of CXCR3 in ovarian cancer cells is mandatory. Our preliminary results show that ovarian cancer cells use CXCR3 to migrate towards malignant ascites. Moreover, tumor cells in peritoneal metastases are invariably CXCR3 overex-pressing regardless of the expression in the primary tumors. Therefore we hypothesize that CXCR3 is involved in the peritoneal spread of ovarian cancer.In the first subproject we want to investigate the influence of CXCR3 on tumorpromoting properties of ovarian cancer cells: proliferation, migration and induction of proteases. This will be validated on primary cultures of ascites-derived tumor cells from patients with ovarian cancer. In a syngeneic orthotopic mouse model of ovarian cancer we want to study the effect of CXCR3 knockdown and intraperitoneal anti-CXCR3 therapy on tumor growth and peritoneal spread. Expression of CXCR3 in lymph node, peritoneal, and omental metastases will be studied in a retrospective cohort of 150 patients with advanced high-grade serous ovarian cancer and correlated with clinicopatho-logic parameters to find further support for the results obtained in vitro and in vivo. In the third subproject we want to identify other chemokine receptors that might be involved in peritoneal metastasis of ovarian cancer based on a screening algorithm.We believe that our results will define CXCR3, and possibly other chemokine receptors, as a new therapeutic target to address pretioneal metastatic spread, the major clinical challenge in advanced ovarian cancer.