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，可导致快速死亡，目前的治疗方法是尼达尼布的酪氨酸激酶抑制作用已被证明是一种成功的治疗方法。然而，由于尼达尼布的非特异性，它是许多肺纤维化疾病的治疗策略。尚不清楚哪些酪氨酸激酶对于驱动纤维化最关键。未来的机制研究应重点关注。识别参与纤维化的特定酪氨酸激酶和细胞类型，这可以实现更精确的靶向我们已确定盘状蛋白结构域受体 2 (DDR2) 是一种有吸引力的促纤维化途径。 DDR2 是一种由纤维状胶原蛋白（如 I 型胶原蛋白）激活的酪氨酸激酶受体。我们最近表明，I 型胶原信号传导可促进成纤维细胞进一步激活，从而导致此外，与 DDR1 不同的是，前馈/正反馈循环最终导致进行性纤维化。许多细胞类型都高度表达，DDR2 表达严重倾斜，在成纤维细胞比其他细胞类型更重要，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对纤维化产生相反的影响，具体取决于具有亲和性的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因此，DDR2 可能会发挥更多作用。成纤维细胞是主要的成纤维效应细胞，最近出现了一种新型的 DDR2 特异性。抑制剂已被证明可以通过抑制癌症相关基因来改善肺癌模型的结果已初步经历间质转化的成纤维细胞和表达 DDR2 的癌细胞。我们发现这种抑制剂也能有效抑制纤维化，我们的初步数据也支持了一种新的发现。 DDR2 信号传导调节 PIK3C2α 的机制，PIK3C2α 是 PI3 激酶的一个鲜为人知的成员该家族最近被证明可以调节 TGFβ 信号转导所必需的 TGFβ 受体内化。 PIK3Cα 也被证明可以调节 PDK1/Akt 信号传导，这与我们关于 DDR2 调节的报告一致最后，最近的一份报告发现，针对成纤维细胞特异性标记物。使用嵌合抗原受体（CAR）-T 细胞方法可有效减轻心脏纤维化。总的来说，这支持了我们的中心假设，即 DDR2 通过成纤维细胞特异性作用促进纤维化 PIK3C2α/TGFβ 信号传导、通过 PIK3C2α/PDK/Akt 信号传导抵抗细胞凋亡以及 DDR2 除了测试 DDR2 的重要性外，它也是抗纤维化治疗的一个有吸引力的目标。小分子抑制剂，鉴于 DDR2 成纤维细胞的高表达，我们将开发 CAR-NK 细胞与 T 细胞不同，NK 细胞不受 MHC 限制，可靶向 DDR2 进行肺纤维化免疫治疗。不进行克隆扩增，因此可以作为现成的治疗解决方案，且用量最少这些研究将增进我们对关键的促纤维化信号通路以及毒性的理解。推进和完善 CAR 免疫疗法治疗纤维化的潜力。