Divergent Roles of MerTK,Tyro3, and Axl in Pancreatic Cancer and Metastasis

MerTK、Tyro3 和 Axl 在胰腺癌和转移中的不同作用

• 批准号: 10601958
• 负责人: H. Shelton Earp
• 金额: $ 53.73万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601958
• 关键词: Acceleration; Antigen Presentation; Apoptotic; Autoimmunity; Biological Availability; Blood; CD4 Positive T Lymphocytes; Cancer Etiology; Cell physiology; Cells; Cessation of life; Chronic; Circulation; Clinical Trials; Complex; Cues; Cytotoxic Chemotherapy; Data; Diagnosis; Disease; Elements; Family; Fibroblasts; Frequencies; Frustration; Gene Expression; Gene Expression Profile; Genetic; Goals; Growth; Heterogeneity; Human; Immune; Immune response; Immunity; Immunologic Monitoring; Immunologics; Immunotherapy; Incidence; Infiltration; Inflammation; Inflammatory Response; Interferons; Ligands; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metastatic Neoplasm to the Liver; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplasms; Operative Surgical Procedures; Oral; Outcome; PD-1 blockade; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Phosphotransferases; Play; Pre-Clinical Model; Radiation therapy; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Role; Signal Transduction; T cell infiltration; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Time; Tumor Immunity; Wild Type Mouse; Work; anti-PD-1; anti-PD1 therapy; attenuation; axl receptor tyrosine kinase; chemotherapy; clinical application; druggable target; effector T cell; efficacy testing; immune cell infiltrate; immunogenic cell death; inhibitor; kinase inhibitor; knockout animal; lymph nodes; monocyte; mouse model; neoplasm immunotherapy; neoplastic cell; novel; pancreatic ductal adenocarcinoma model; paracrine; phase I trial; pre-clinical; prevent; programs; response; restraint; single cell sequencing; small molecule inhibitor; success; synergism; targeted treatment; therapy resistant; trafficking; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; tumorigenic

ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is perhaps the most recalcitrant human neoplasm. With 10% overall 5-year survival and an increasing incidence, PDAC will be the second leading cause of cancer deaths within a decade. The constellation of chemo- and targeted therapy resistant tumor cells, and a tumor microenvironment featuring suppressive innate immune cells and fibroblasts frustrates therapeutic success. PDAC and preclinical PDAC models both show a massive myeloid and fibroblast cell infiltration which suppresses effector T cells and promotes metastases. Our data implicate a family of receptor tyrosine kinases Tyro3, Axl, MerTK (TAM RTKs) in directing pro-tumorigenic polarization of CAFs and myeloid cells in PDAC. The homeostatic role of myeloid cell TAM RTKs is to coordinate suppression of innate immune inflammatory responses to apoptotic material preventing chronic inflammation and autoimmunity. Our preliminary data, show that TAM RTKs play non- redundant and sometimes opposing functions in the PDAC tumor microenvironment (TME), leading to polarization of myeloid cells and fibroblasts. Clinical trials of TAM RTK inhibition are beginning; thus, our work to understand the consequences and mechanism of inhibition for each TAM RTK is both timely and significant. Host MerTK and Tyro3 in wild type mice promote PDAC growth and contribute to lack of responsiveness to anti- PD1 therapy, as germline MerTK or Tyro3 deletion slow PDAC growth, markedly reduces liver metastasis, and promotes anti-PD-1 efficacy. However, in the Axl-/- mice there is an unexpected increase in metastatic outgrowth. Our group has synthesized orally bioavailable, selective MerTK kinase inhibitors, which recapitulate aspects of MerTK and/or Tyro3 genetic loss. Lastly our preliminary studies in patients identify MerTK+ and Tyro3+ myeloid cells and document an increase in MerTK+/Tyro3+ MDSCs in the blood of PDAC patients. Hypothesis. MerTK+ and/or Tyro3+ monocytes, macrophages, MDSCs, and Tyro3+ fibroblasts are expanded in PDAC, and have at least some separate roles in the suppressive TME and metastasis promotion. Our Specific Aims are: Aim 1: To determine how MerTK and Tyro3 act in the innate immune compartment to accelerate PDAC growth and metastasis and how Axl has the opposite effect. Aim 2: To determine the role of Tyro3 in PDAC cancer associated fibroblasts and Aim 3: To evaluate the therapeutic potential of targeting TAM RTKs in PDAC in preclinical PDAC models (using UNC inhibitors one of which is in Phase 1 trials) in combination with other cytotoxic and immune therapies. We will quantify, functionally characterize, and study gene expression signature of MerTK+ and Tyro3+ myeloid cells in the circulation, tumors and lymph nodes and fibroblast cells in the PDAC patient tumors before and during therapy. Success would represent a significant advance toward understanding how to make immunologically “cold” PDAC tumors “hot” and responsive to immunotherapy.

抽象的 胰腺导管腺癌 (PDAC) 可能是最顽固的人类肿瘤，占总体的 10%。 5 年生存率和发病率不断上升，PDAC 将成为未来癌症死亡的第二大原因 化疗和靶向治疗耐药的肿瘤细胞群以及肿瘤微环境。 以抑制性先天免疫细胞和成纤维细胞为特征，会阻碍 PDAC 和临床前的成功。 PDAC 模型均显示大量骨髓细胞和成纤维细胞浸润，抑制效应 T 细胞和 我们的数据表明受体酪氨酸激酶 Tyro3、Axl、MerTK (TAM RTK) 家族会促进转移。 指导 PDAC 中 CAF 和骨髓细胞的促肿瘤极化 骨髓细胞的稳态作用。 细胞 TAM RTK 协调抑制对凋亡物质的先天免疫炎症反应 我们的初步数据表明，TAM RTK 具有非-预防慢性炎症和自身免疫的作用。 PDAC 肿瘤微环境 (TME) 中存在冗余且有时相反的功能，导致 TAM RTK 抑制的临床试验正在开始； 了解每个 TAM RTK 的抑制后果和机制既及时又有意义。 野生型小鼠中的宿主 MerTK 和 Tyro3 促进 PDAC 生长并导致缺乏抗 PD1 疗法，因为种系 MerTK 或 Tyro3 缺失会减缓 PDAC 的生长，从而显着减少肝转移，并且 促进抗 PD-1 功效然而，在 Axl-/- 小鼠中，转移性出现意想不到的增加。 我们的小组已经合成了口服生物可利用的选择性 MerTK 激酶抑制剂，其概括如下： MerTK 和/或 Tyro3 基因缺失方面，我们对患者的初步研究最终确定了 MerTK+ 和 Tyro3+。 骨髓细胞并记录了 PDAC 患者血液中 MerTK+/Tyro3+ MDSC 的增加。 假设 MerTK+ 和/或 Tyro3+ 单核细胞、巨噬细胞、MDSC 和 Tyro3+ 成纤维细胞在 PDAC，并且在抑制性 TME 和促进转移中至少具有一些单独的作用。 目标是： 目标 1：确定 MerTK 和 Tyro3 如何在先天免疫区室中发挥作用以加速 PDAC 的生长和转移以及 Axl 如何产生相反的作用 目标 2：确定 Tyro3 在其中的作用。 PDAC 癌症相关成纤维细胞和目标 3：评估靶向 TAM RTK 的治疗潜力 临床前 PDAC 模型中的 PDAC（使用 UNC 抑制剂，其中之一处于第一阶段试验）与 我们将量化、功能表征和研究基因表达。 循环系统、肿瘤和淋巴结中的 MerTK+ 和 Tyro3+ 骨髓细胞以及成纤维细胞的特征 治疗前和治疗期间的 PDAC 患者肿瘤的成功将代表着朝着这一目标迈出的重大进展。 了解如何使免疫学上“冷”的 PDAC 肿瘤变得“热”并对免疫疗法产生反应。