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

卵巢癌免疫干预成功的基本前提是肿瘤抑制性淋巴细胞充分浸润肿瘤。它们的趋化性募集由CXCR3趋化因子受体及其配体CXCL9、CXCL10和CXCL11介导。我们已经发现，卵巢癌中CXCR3趋化因子的高表达与大量肿瘤浸润淋巴细胞和总生存率的提高有关。为了逃避免疫系统，肿瘤细胞可以产生能够切割和灭活肿瘤内趋化因子的蛋白酶。与我们的国际合作伙伴一起，我们已经将CXCL9确定为激肽释放酶相关肽酶4（KLK 4）的高亲和力靶标。此外，已知CXCR3配体作为切割的趋化因子存在于人卵巢癌中。由于KLK 4在人类卵巢癌中过表达，但生理上仅在发育中的牙齿和前列腺中表达，我们推测KLK 4可能代表了一个非常特异的药理学靶点，以改善免疫治疗（例如检查点抑制）为了验证这一假设，我们将进一步表征CXCL9和其他CXCR3趋化因子的切割，KLK4和其他KLK。主要的焦点是这些裂解对趋化能力的影响。在卵巢癌的同基因小鼠模型中，我们接下来将研究肿瘤细胞中KLK 4过表达或敲除对淋巴细胞浸润、肿瘤生长和转移的影响。此外，我们将探讨免疫系统的相关性，特别是CXCR3受体，观察到的效果。通过使用已建立的KLK 4抑制剂，我们可以进一步模拟抗KLK 4治疗及其对肿瘤生长和免疫干预的影响。在一个大的人类卵巢癌队列的回顾性分析中，我们将最终测试，如果KLK 4的表达水平与肿瘤浸润淋巴细胞的数量和生存在人类卵巢cancer.The结果是负相关的，第一次，描述KLK 4在实体恶性肿瘤的免疫调节功能，并将其定义为一个新的治疗靶点，以提高免疫干预卵巢癌。

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.