Role of RON kinase in anti-tumor immune responses

项目摘要/摘要 背景：我们的工作已经确定RON受体酪氨酸激酶是乳房的关键介质 肿瘤在人和小鼠体内转移，但RON在肿瘤转移中的作用机制尚不清楚。我们 最近发现，RON在肿瘤转移中的关键作用不在于肿瘤本身，而在于宿主 免疫系统。宿主中RON的激活允许转移的肿瘤细胞逃避免疫监视- 促进转移的发展。在宿主中特异的RON激酶结构域的基因缺失，或 药物抑制RON，通过促进CD8 T细胞反应来防止肿瘤转移 杀死了转移细胞。有趣的是，RON在免疫系统中的表达仅限于常驻(而不是骨骼 骨髓来源的)组织巨噬细胞，表明这些特化细胞在 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 对早期转移性殖民和/或生长的破坏性侮辱的响应者，他们可能扮演 在塑造随后的免疫反应中起着基础性作用。我们建议罗恩调节免疫- 在转移过程中驻留巨噬细胞的抑制开关，抑制RON恢复免疫- 居间杀人。我们的初步数据表明，RON上调PD-L1 T细胞检查点的表达 常驻巨噬细胞中的配体和促肿瘤细胞因子。事实上，初步结果表明， 联合抑制RON和辅助性T细胞检查点抑制物抗CTLA4是非常有效的 在刺激免疫反应和根除肿瘤方面。我们假设罗恩-施特劳斯 巨噬细胞通过MAPK依赖的免疫抑制程序抑制CD8 T细胞功能 调节PD-L1和促肿瘤细胞因子。我们将通过执行三个例子来检验这一假设 具体目标：首先，我们将确定RON抑制剂ASLAN002是否改善了对抗CTLA-4的反应 转移性乳腺癌模型的免疫治疗。其次，我们将确定髓系特异性缺失是否 RON激酶可阻断乳腺肿瘤的转移。第三，我们将确定RON是否调节CD8 T细胞 通过MAPK信号转导和上调PD-L1进行抑制。了解RON的生物学原理 在肿瘤免疫反应中的作用，以及RON抑制剂如何在治疗环境中有用，是 对于优化临床试验设计和最大限度地为患者带来好处至关重要。RON抑制剂ASLAN002正在试验中 和良好的容忍度，所以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.