Targeting Fibroblast Discoidin Domain Receptor 2 for Immunotherapy to Pulmonary Fibrosis

靶向成纤维细胞盘状结构域受体 2 用于肺纤维化免疫治疗

基本信息

批准号：
10362183
负责人：
KEVIN KEEWOUN KIM
金额：
$ 61.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362183
关键词：
1-Phosphatidylinositol 3-Kinase Acute Lung Injury Acute Respiratory Distress Syndrome Antibodies Ants Apoptosis Attenuated Automobile Driving Binding CD94 Antigen Cells Cessation of life Clonal Expansion Collagen Collagen Type I DDR1 gene Data Disease Effector Cell Epithelial Cells Family Feedback Fibrillar Collagen Fibroblasts Fibrosis Future Immunotherapy Lead Lung diseases Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Modeling Mus Natural Killer Cells PDPK1 gene Pathway interactions Peptides Pharmacology Phosphatidylinositide 3-Kinase Inhibitor Phosphorylation Profibrotic signal Protein Tyrosine Kinase Pulmonary Fibrosis Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Reporting Resistance Safety Signal Pathway Signal Transduction Surface Syndrome System Systemic Scleroderma T-Lymphocyte Technology Testing Therapeutic Toxic effect Transforming Growth Factor beta Tyrosine Kinase Inhibitor antifibrotic treatment cancer cell cell type chimeric antigen receptor chimeric antigen receptor T cells clinical effect coronary fibrosis discoidin domain receptor 2 engineered NK cell fibrotic lung idiopathic pulmonary fibrosis improved outcome inhibitor member nintedanib novel partial response phosphoproteomics receptor internalization selective expression small molecule inhibitor success therapeutic target

项目摘要

Progressive pulmonary fibrosis is a devastating condition that can lead to rapid death and current therapy is only modestly effective. Tyrosine kinase inhibition with Nindedanib has proven to be a successful therapeutic strategy for a number of pulmonary fibrosis disorders. However, due to the nonspecificity of Nintedanib it is unclear which tyrosine kinases are most critical for driving fibrosis. Future mechanistic studies should focus on identifying specific tyrosine kinases and cell types involved in fibrosis which may enable more precise targeting of critical pro-fibrotic pathways. We have identified discoidin domain receptor 2 (DDR2) as an attractive therapeutic target. DDR2 is a tyrosine kinase receptor activated by fibrillar collagens such as type I collagen and we have recently shown that type I collagen signaling promotes further fibroblast activation leading to a feed forward/postive feedback loop culminating in progressive fibrosis. Furthermore, unlike DDR1, which is highly expressed by many cell types, DDR2 expression is heavily skewed with much higher expression on fibroblasts than other cell types. This is critical because we have recently reported that activation of ubiquitous intracellular signaling pathways can have opposing effects on fibrosis depending on the cell type with pro- fibrotic activation within fibroblasts but anti-fibrotic effects within epithelial cells. Thus, DDR2 may enable more specific targeting of fibroblasts which are the primary fibrogenic effector cells. Recently a novel DDR2-specific inhibitor has been shown to improve outcome in a model of lung cancer through inhibition of cancer associated fibroblasts and DDR2-expressing cancer cells which have undergone mesenchymal transition. In preliminary data we find that this inhibitor is also effective at inhibiting fibrosis. Our preliminary data also support a novel mechanism by which DDR2 signaling regulates PIK3C2α, a poorly understood member of the PI3 kinase family which has recently been shown to regulate TGFβ receptor internalization necessary for TGFβ signaling. PIK3Cα has also been shown to regulate PDK1/Akt signaling consistent with our report that DDR2 regulates fibroblast survival through PDK1/Akt. Finally, a recent report found that targeting fibroblast specific markers using a chimeric antigen receptor (CAR)-T cell approach was effective at attenuating cardiac fibrosis. Collectively, this support our central hypothesis that DDR2 promotes fibrosis through fibroblast specific effects on PIK3C2α/TGFβ signaling, resistance to apoptosis via PIK3C2α/PDK/Akt signaling and that DDR2 represents an attractive target for anti-fibrotic therapy. In addition to testing the importance of DDR2 with a small molecule inhibitor, given skewed high fibroblast expression of DDR2, we will develop CAR-NK cells targeting DDR2 for immunotherapy of pulmonary fibrosis. Unlike T cells, NK cells are not MHC restricted, do not undergo clonal expansion and may therefore serve as off-the shelf therapeutic solution with minimum toxicity. These studies will advance our understanding of a critical pro-fibrotic signaling pathway as well as advance and refine the potential for adapting CAR immunotherapy for fibrosis.

进行性肺纤维化是一种毁灭性的疾病，可能导致快速死亡，当前治疗是仅适度有效。 Nondenab抑制酪氨酸激酶已被证明是一种成功的疗法许多肺纤维化障碍的策略。但是，由于Nintedanib的非特异性，这是尚不清楚哪种酪氨酸激酶对于驱动纤维化最重要。未来的机械研究应关注识别纤维化涉及的特定酪氨酸激酶和细胞类型，这可能会实现更精确的靶向关键的促纤维途径。我们已经确定盘状蛋白域受体2（DDR2）是一个吸引人治疗靶标。 DDR2是一种酪氨酸激酶受体，由原纤维胶原（例如I型胶原蛋白）激活我们最近表明，I型胶原蛋白信号传导促进了进一步的成纤维细胞激活导致进食前进/后反馈回路最终在进行性纤维化中。此外，与DDR1不同， DDR2表达高度表达了许多细胞类型的表达，并以更高的表达在成纤维细胞比其他细胞类型。这很关键，因为我们最近报道了无处不在的激活细胞内信号通路可能会对纤维化产生相反的影响，具体取决于细胞类型成纤维细胞内的纤维化激活，但上皮细胞内的抗纤维化作用。那，DDR2可能会启用更多成纤维细胞的特定靶向是主要的纤维效应细胞。最近是一种新颖的DDR2特异性已证明抑制剂可以通过抑制癌症的肺癌模型改善结果具有杂质转变的成纤维细胞和表达DDR2的癌细胞。在初步数据我们发现该抑制剂也可以有效抑制纤维化。我们的初步数据也支持一本小说 DDR2信号传导调节PIK3C2α的机制，PIK3C2α是PI3激酶的知识较低的成员最近已证明该家族调节TGFβ受体内在化的TGFβ信号传导所必需的家族。还显示PIK3Cα调节PDK1/AKT信号与我们的报告调节的报告一致成纤维细胞通过PDK1/AKT生存。最后，最近的一份报告发现，针对成纤维细胞特定标记使用嵌合抗原受体（CAR）-T细胞方法可有效减弱心脏纤维化。总体而言，这支持了我们的中心假设，即DDR2通过成纤维细胞特异性效应促进纤维化在PIK3C2α/TGFβ信号传导上，通过PIK3C2α/PDK/AKT信号传导对凋亡的抗性和DDR2 代表了抗纤维化治疗的有吸引力的靶标。除了测试DDR2的重要性外小分子抑制剂，鉴于DDR2偏斜的高成纤维细胞表达，我们将发展CAR-NK细胞靶向DDR2用于肺纤维化的免疫疗法。与T细胞不同，NK细胞不受MHC的限制，DO 不经历克隆膨胀，因此可以用作货架治疗溶液的最小毒性。这些研究将促进我们对关键促纤维化信号通路以及提前并完善了适应汽车免疫疗法以进行纤维化的潜力。