An innate immune checkpoint in cancer immunotherapy

癌症免疫疗法试图增强人体自身的防御机制--免疫系统--以杀死 癌细胞和战胜癌症。使用T细胞检查点抑制剂的免疫疗法有望带来革命性的变化 癌症治疗。然而，这些疗法的一个主要局限性是，它们只在以下几个方面有效 病人。最近的证据表明，肿瘤中T细胞浸润增强是一种预测标记物 对T细胞检查点抑制剂呈阳性反应。因此，对T细胞检查点抑制剂的反应失败可能 与先天免疫系统有效参与适应性抗肿瘤能力的缺陷相对应 免疫反应。在小鼠身上，我们已经识别并禁用了一种新的免疫检查点机制，一种细胞 一种名为MERTK的蛋白质，存在于先天性免疫细胞中--人体的第一道免疫防线。MerTK 限制先天免疫细胞被激活的程度，进而控制总体 免疫反应将是。我们还检测到MERTK在肿瘤相关的先天组织中的存在 人体样本中的免疫细胞。在小鼠癌症模型中，MerTK的基因消融导致戏剧性的 防止癌症生长。我们建议(I)使用小鼠癌症模型来研究其机制/S MERTK功能丧失可提高抗肿瘤免疫功能：(Ii)急性消融MerTK后， 已建立的肿瘤及其激酶活性的失活足以克服未能触发抗- 肿瘤T细胞反应和抑制肿瘤生长，以及(Iii)探讨MERTK与 患者对T细胞检查点抑制剂的激活和耐药性。通过这些研究，我们将更好地 了解当MERTK刹车被移除时，免疫系统如何抗击癌症，获得证据- 抑制MERTK的药物治疗使用的概念，并开发一种可预测的生物标志物小组 确定可能对MERTK抑制剂有反应的患者子集。总而言之，我们的 拟议的研究可能会确定一种新的癌症免疫治疗靶点，这种靶点本身或在 与FDA批准的检查点抑制剂或分子靶向治疗相结合，可以显著 提高对抗癌治疗有客观反应的患者比例。

Cancer immunotherapy attempts to boost the body’s own defense mechanism – the immune system – to kill cancer cells and defeat cancer. Immunotherapy with T cell checkpoint inhibitors is promising to revolutionize cancer therapy. However, a major limitation of these therapies is that they are effective in only a subset of patients. Recent evidence suggests that enhanced T cell infiltration in the tumor is a predictive marker of positive response to T cell checkpoint inhibitors. Thus, failure to respond to T cell checkpoint inhibitors may correspond to a defect in the ability of the innate immune system to effectively engage adaptive anti-tumor immune response. In mice, we have identified and disabled a novel immune checkpoint mechanism, a cellular protein named MERTK, that is found in innate immune cells – the body’s first line of immune defense. MERTK limits the extent to which innate immune cells can get activated, which in turn controls how much the overall immune response would be. We have also detected the presence of MERTK in tumor-associated innate immune cells in human samples. In mouse models of cancer, genetic ablation of Mertk results in dramatic prevention of cancer growth. We propose to (i) use mouse models of cancers to investigate the mechanism/s by which loss of MERTK function improves anti-tumor immunity, (ii) test if acute ablation of Mertk in established tumors and the inactivation of its kinase activity are sufficient to overcome the failure to trigger anti- tumor T cell responses and restrict tumor growth, and (iii) to investigate the association between MERTK activation and the resistance to T cell checkpoint inhibitors in patients. Through these studies, we will better understand how the immune system can fight cancer when the MERTK brake is removed, obtain proof-of- concept for therapeutic use of drugs that would inhibit MERTK, and develop a predictive biomarker panel for the identification of a subset of patients that are likely to respond to MERTK inhibitors. In summary, our proposed studies can potentially identify a novel target for cancer immunotherapy that by itself, or in combination with FDA-approved checkpoint inhibitors or molecular targeted therapies, could significantly increase the percentage of patients that show objective response to anti-cancer therapy.