Role of RON kinase in anti-tumor immune responses

项目概要/摘要 背景：我们的工作已经证实罗恩受体酪氨酸激酶是乳腺癌的关键介质， 在人类和小鼠中的癌症转移，但是罗恩在转移中的作用机制仍然不清楚。我们 最近发现，罗恩在转移中的关键作用并不在于肿瘤本身，而在于宿主 免疫系统宿主体内罗恩的激活使转移性肿瘤细胞逃避免疫监视- 促进转移的发展。在宿主中特异性遗传缺失罗恩激酶结构域，或 药理学罗恩抑制通过促进CD 8 + T细胞反应来防止转移瘤的生长， 杀死转移细胞。有趣的是，罗恩在免疫系统中的表达仅限于居民（而不是骨 骨髓来源的）组织巨噬细胞，表明这些特化细胞在细胞分化中的作用未被充分认识。 通过免疫调节调节肿瘤转移。我们设想，常驻巨噬细胞是“第一个”， 反应者”对早期转移性定植和/或生长的破坏性损伤，并且它们可能发挥 在形成随后的免疫反应中起着重要作用。我们认为罗恩调节免疫系统- 抑制转移过程中驻留巨噬细胞中的转换，抑制罗恩恢复免疫- 中介杀人我们的初步数据表明，罗恩上调PD-L1 T细胞检查点的表达 配体和肿瘤促进细胞因子在常驻巨噬细胞。事实上，初步结果表明， 联合抑制罗恩与互补的T细胞检查点抑制剂，抗CTLA 4，是非常有效的 刺激免疫反应和根除肿瘤。我们假设Ron表达 巨噬细胞通过MAPK依赖性免疫抑制程序抑制CD 8 + T细胞功能 调节PD-L1和肿瘤促进细胞因子。我们将通过执行三个测试来验证这一假设。 具体目标：首先，我们将确定罗恩抑制剂ASLAN 002是否改善对抗CTLA-4的反应 转移性乳腺癌模型的免疫治疗。第二，我们将确定是否骨髓特异性缺失， 罗恩激酶阻断乳腺肿瘤转移。第三，我们将确定罗恩是否调节CD 8 + T细胞 通过MAPK信号传导和PD-L1上调的抑制。了解罗恩 在肿瘤免疫反应中的作用，以及罗恩抑制剂如何在治疗环境中发挥作用， 这对于优化临床试验设计和最大化患者获益至关重要。罗恩抑制剂ASLAN 002正在试验中 并且耐受性良好，因此我们的工作可以产生短期影响。

Project Summary/abstract Background: Our work has established that the Ron receptor tyrosine kinase is a key mediator of breast cancer metastasis in humans and mice, but the mechanisms of Ron function in metastasis are still unclear. We recently discovered that the key function of Ron in metastasis is not in the tumor itself, but is in the host immune system. Activation of Ron in the host allows metastatic tumor cells to escape immune surveillance – facilitating development of metastases. Genetic deletion of the Ron kinase domain specifically in the host, or pharmacologic Ron inhibition, prevented outgrowth of metastases by promoting a CD8+ T cell response that killed metastatic cells. Interestingly, Ron expression in the immune system is restricted to resident (not bone marrow-derived) tissue macrophages, indicating that these specialized cells have an under-appreciated role in regulating metastasis of tumors through immune regulation. We envision that resident macrophages are “first responders” to the disruptive insult of early metastatic colonization and/or growth, and that they may play a fundamental role in shaping subsequent immune responses. We propose that Ron regulates an immune- suppressive switch in resident macrophages during metastasis, and that inhibiting Ron reinstates immune- mediated killing. Our preliminary data indicate that Ron upregulates expression of the PD-L1 T cell checkpoint ligand and tumor-promoting cytokines in resident macrophages. Indeed, preliminary results show that combined inhibition of Ron with a complementary T cell checkpoint inhibitor, anti-CTLA4, is extremely effective in stimulating immune responses and eradicating tumors. We hypothesize that that Ron-expressing macrophages suppress CD8+ T cell function through a MAPK-dependent immunosuppressive program regulating PD-L1 and tumor-promoting cytokines. We will test this hypothesis through execution of three specific aims: First, we will determine if the Ron inhibitor ASLAN002 improves response to anti-CTLA-4 immunotherapy in metastatic breast cancer models. Second, we will determine if myeloid-specific deletion of Ron kinase blocks metastasis of mammary tumors. Third, we will determine if Ron regulates CD8+ T cell suppression through MAPK signaling and upregulation of PD-L1. Understanding the biology of how Ron functions in the immune response to tumors, and how Ron inhibitors can be useful in the treatment setting, is critical to optimize clinical trial design and maximize benefit to patients. The Ron inhibitor ASLAN002 is in trials and well tolerated, so our work can have near-term impact.