Kallikrein-related peptidase 4 (KLK4) as a new target toimprove immune intervention in ovarian cancer

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The fundamental prerequisite for a successful immune intervention in ovarian cancer is a sufficient infiltration of the tumor with tumor-suppressive lymphocytes. Their chemotactic recruitment is mediated by the CXCR3 chemokine receptor and its ligands CXCL9, CXCL10 and CXCL11. We have already shown that a high expression of these CXCR3 chemokines in ovarian cancer is associated with a high number of tumor-infiltrating lymphocytes and an improved overall survival. In order to evade the immune system, tumor cells can produce proteases capable of cleaving and inactivating intratumoral chemokines. Together with our international collaboration partners we have identified CXCL9 as a high-affinity target for kallikrein-related peptidase 4 (KLK4). Moreover, it is known that CXCR3 ligands are present as cleaved chemokines in human ovarian cancer. As KLK4 is overexpressed in human ovarian cancer, but physiologically only expressed in developing teeth and the prostate, we postulate that KLK4 may represent a very specific pharmacological target to improve immunotherapy (e.g. checkpoint inhibition) in ovarian cancer by enhancing the intratumoral concentrations of active CXCR3 chemokines.To test this hypothesis we will further characterize the cleavage of CXCL9 and the other CXCR3 chemokines by KLK4 and also other KLKs. The main focus is the impact of these cleavages on the chemotactic capacity. In a syngeneic mouse model of ovarian cancer, we will next study the effect of KLK4 overexpression or knockout in the tumor cells on lymphocytic infiltration, tumor growth and metastasis. Moreover, we will explore the relevance of the immune system in general, and of the CXCR3 receptor in particular, for the observed effects. By using established KLK4 inhibitors, we can furthermore simulate an anti-KLK4 therapy and its impact on tumor growth and immune intervention. In a retrospective analysis of a large cohort of human ovarian cancers, we will finally test, if KLK4 expression levels are inversely associated with the number of tumor-infiltrating lymphocytes and survival in human ovarian cancer.The results are intended to delineate, for the first time, immunomodulatory functions of KLK4 in solid malignancies and to define it as a new therapeutic target to improve immune intervention in ovarian cancer.